Substituted aryl 1,4-pyrazine derivatives

ABSTRACT

Substituted aryl 1,4-pyrazine derivatives and their use in treating anxiety disorders, depression and stress related disorders are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisionalapplication Serial No. 60/332,052 filed on Nov. 21, 2001, under 35 USC119(e)(i); U.S. provisional application Serial No. 60/358,546 filed onFeb. 21, 2002, under 35 USC 119(e)(i); U.S. provisional applicationSerial No. 60/388,285 filed on Jun. 13, 2002, under 35 USC 119(e)(i);U.S. provisional application Serial No. 60/410,378 filed on Sep. 13,2002, under 35 USC 119(e)(i), which are incorporated herein by referencein their entirety.

FIELD OF THE INVENTION

[0002] This invention relates to substituted aryl 1,4-pyrazinederivatives and processes for preparing them, pharmaceuticalcompositions containing them, and methods of using them to treat adisorder or condition which can be effected or facilitated byantagonizing a CRF receptor, including but not limited to disordersinduced or facilitated by CRF, such as anxiety disorders, and depressionand stress related disorders. Additionally this invention relates to theuse of such compounds as probes for the localization of CRF₁ receptorsin cells or tissues.

BACKGROUND OF THE INVENTION

[0003] Corticotropin releasing factor (CRF) is a 41 amino acid peptidethat is the primary physiological regulator of proopiomelanocortin(POMC) derived peptide secretion from the anterior pituitary gland [J.Rivier et al., Proc. Natl. Acad. Sci (USA) 80:4851 (1983); W. Vale etal., Science 213:1394 (1981)]. In addition to its endocrine role at thepituitary gland, immunohistochemical localization of CRF hasdemonstrated that the hormone has a broad extrahypothalamic distributionin the central nervous system and produces a wide spectrum of autonomic,electrophysiological and behavioral effects consistent with aneurotransmitter or neuromodulator role in the brain [W. Vale et al.,Rec. Prog. Horm. Res. 39:245 (1983); .F. Koob, Persp. Behav. Med. 2:39(1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There isalso evidence that CRF plays a significant role in integrating theresponse in the immune system to physiological, psychological, andimmunological stressors [J. E. Blalock, Physiological Reviews 69:1(1989); J. E. Morley, Life Sci. 41:527 (1987)].

[0004] There is evidence that CRF has a role in psychiatric disordersand neurological diseases including depression, anxiety-relateddisorders and feeding disorders. A role for CRF has also been postulatedin the etiology and pathophysiology of Alzheimer's disease, Parkinson'sdisease, Huntington's disease, progressive supranuclear palsy andamyotrophic lateral sclerosis, as they relate to the dysfunction of CRFneurons in the central nervous system [for a review, see: E. B. DeSouze, Hosp. Practice 23:59 (1988)].

[0005] Anxiety disorders are a group of diseases, recognized in the art,that includes phobic disorders, anxiety states, post-traumatic stressdisorder and atypical anxiety disorders [The Merck Manual of Diagnosisand Therapy, 16^(th) edition (1992)]. Emotional stress is often aprecipitating factor in anxiety disorders, and such disorders generallyrespond to medications that lower response to stress.

[0006] In affective disorder, or major depression, the concentration ofCRF is significantly increased in the cerebral spinal fluid (CSF) ofdrug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984);C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France etal., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol. Psychiatry25:355 (1989)]. Furthermore, the density of CRF receptors issignificantly decreased in the frontal cortex of suicide victims,consistent with a hypersecretion of CRF [C. B. Memeroff et al., Arch.Gen. Psychiatry 45:577 (1988)]. In addition, there is a bluntedadrenocorticotropin (ACTH) response to CRF (i.v. administered) observedin depressed patients [P. W. Gold et al., Am. J. Psychiatry 141:619(1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W.Gold et al., New Engl. J. Med. 314:1129 (1986)]. Preclinical studies inrats and non-human primates provide additional support for thehypothesis that hypersecretion of CRF may be involved in the symptomsseen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047(1989)]. There is also preliminary evidence that tricyclicantidepressants can alter CRF levels and thus modulate the numbers ofreceptors in the brain [Grigoriadis et al., Neuropsychopharmacology 2:53(1989)].

[0007] CRF has also been implicated in the etiology of anxiety-relateddisorders, and is known to produce anxiogenic effects in animals.Interactions between benzodiazepine/non-benzodiazepine anxiolytics andCRF have been demonstrated in a variety of behavioral anxiety models [D.R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using theputative CRF receptor antagonist α-helical ovine CRF (9-41) in a varietyof behavioral paradigms demonstrates that the antagonist produces“anxiolytic-like” effects that are qualitatively similar to thebenzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393(1987), Brain Research Reviews 15:71 (1990)].

[0008] Neurochemical, endocrine and receptor binding studies have alldemonstrated interactions between CRF and benzodiazepine anxiolytics,providing further evidence for the involvement of CRF in thesedisorders. Chlodiazepoxide attenuates the “anxiogenic” effects of CRFboth in the conflict test [K. T. Britton et al., Psychopharmacology86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)]and in the acoustic startle test [N. R. Swerdlow et al.,Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptorantagonist Ro 15-1788, which was without behavioral activity alone inthe operant conflict test, reversed the effects of CRF in adose-dependent manner while the benzodiazepine inverse agonist FG 7142enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology94:396 (1988)]. The mechanisms and sites of action through whichconventional anxiolytics and antidepressants produce their therapeuticeffects remain to be elucidated. Preliminary studies, examining theeffects of a CRF₁ receptor antagonist peptide (α-helical CRF₉₋₄₁) in avariety of behavioral paradigms, have demonstrated that the CRF₁antagonist produces “anxiolytic-like” effects qualitatively similar tothe benzodiazepines [for a review, see: G. F. Koob and K. T. Britton,In: Corticotropin-Releasing Factor: Basic and Clinical Studies of aNeuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p.221(1990)].

[0009] The use of CRF₁ antagonists for the treatment of Syndrome X hasalso been described in U.S. patent application Ser. No. 09/696,822,filed Oct. 26, 2000, and European Patent Application No. 003094414,filed Oct. 26, 2000, which are also incorporated in their entiretiesherein by reference. Methods for using CRF₁ antagonists to treatcongestive heart failure are described in U.S. Ser. No. 09/248,073,filed Feb. 10, 1999, now U.S. Pat. No. 6,043,260 (Mar. 28, 2000) whichis also incorporated herein in its entirety by reference.

[0010] CRF is known to have a broad extrahypothalmic distribution in theCNS, contributing therein to a wide spectrum of autonomic behavioral andphysiological effects [see, e.g., Vale et al., 1983; Koob, 985; and E.B. De Souze et al., 1985]. For example, CRF concentrations aresignificantly increased in the cerebral spinal fluid of patientsafflicted with affective disorder or major depression [see, e.g.,Nemeroff et al., 1984; Banki et al., 1987; France et al., 1988; Arato etal., 1989]. Moreover, excessive levels of CRF are known to produceanxiogenic effects in animal models [see, e.g., Britton et al., 1982;Berridge and Dunn, 1986 and 1987], and CRF₁ antagonists are known toproduce anxiolytic effects; accordingly, therapeutically effectiveamounts of compounds provided herein are, for example, determined byassessing the anxiolytic effects of varying amounts of the compounds insuch animal models.

[0011] The following patents or patent applications disclose compoundsas antagonists of CRF₁ receptors: WO0160806, WO9735901, WO9829119,WO9736886, WO9736898, and U.S. Pat. Nos. 5,872,136, 5,880,140, and5,883,105. The compounds are useful for treating CNS-related disorders,particularly affective disorders and acute and chronic neurologicaldisorders.

SUMMARY OF THE INVENTION

[0012] We have found that compounds of Formula I, as well asstereoisomers thereof, pharmaceutically acceptable salts thereof, andprodrugs thereof, are CRF₁ antagonists and are useful in the treatmentof disorders and diseases associated with CRF₁ receptors, includingCNS-related disorders and diseases, particularly psychiatric disorders,affective disorders such as anxiety disorders, depression and stressrelated disorders, and acute and chronic neurological disorders anddiseases. The compounds are also useful in smoking cessation programs.

[0013] Thus, in a first aspect, this invention provides a compound ofFormula I,

[0014] or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, or a prodrug thereof, wherein in Formula I:

[0015] X is selected from —NR₃R₄, —OR₃, —CR₃R₅R₅, —C(O)R₃, —S(O)_(m)R₃,—NR₃C(O)R₄, or —NR₃S(O)_(m)R₄;

[0016] m is 0,1 or 2;

[0017] Ar is selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

[0018] R₁, R₂, and R₅ are independently selected from halogen, —NO₂,—CN, —R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a) —S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a);

[0019] R₃ and R₄ are independently selected from R_(a,)heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl,substituted aryl, aryl cycloalkyl, substituted aryl cycloalkyl,heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, arylheterocycloalkyl, substituted aryl heterocycloalkyl, heteroarylheterocycloalkyl, or substituted heteroaryl heterocycloalkyl provided atleast one of R₃ or R₄ are heteroaryl, substituted heteroaryl, arylcycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl,substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substitutedaryl heterocycloalkyl, heteroaryl heterocycloalkyl, substitutedheteroaryl heterocycloalkyl, heterocycloalkyl or substitutedheterocycloalkyl;

[0020] R_(a) each is selected from H, alkyl, cycloalkyl, haloalkyl,aryl, heteroaryl, or heterocycloalkyl optionally substituted with 1 to 5of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O), thione (═S),phenyl, heteroaryl, or heterocycloalkyl where phenyl, heteroaryl, andheterocycloalkyl are optionally substituted with 1 to 5 independentlytaken from R_(t);

[0021] R_(t) each is selected from H, halogen, —NO₂, —NH₂, —OH, —SH,—CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl, NHalkyl,Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl and SO₂Nalkylalkyl,alkyl, cycloalkyl, haloalkyl, phenyl, benzyl, heteroaryl, orheterocycloalkyl where phenyl, benzyl heteroaryl and heterocycloalkylmay be optionally substituted with alkyl or halogen; and

[0022] Aryl is either phenyl or naphthyl,

[0023] provided that the compound is not:

[0024]2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-methylpiperidin-4-yl)oxy]pyrazine

[0025]2,5-dimethyl-3-(2,4-dichlorophenyl)-6-(tetrahydrofuran-3-yl)oxy]pyrazine

[0026]2,5-dimethyl-3-(2,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-4-yloxy)pyrazine

[0027]2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-methylpiperidin-3-yl)oxy]pyrazine

[0028]2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-ethylpiperidin-3-yl)oxy]pyrazine

[0029]2,5-dimethyl-3-(2,4-dichlorophenyl)-6-(1-piperidin-4-yl)oxy]pyrazine

[0030] 2,5-dimethyl-3-(2,4-dichlorophenyl)-6-piperidin-3-yl)oxy]pyrazine

[0031]2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-ethylpyrrolidin-3-yl)oxy]pyrazine

[0032]2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-methylpyrrolidin-3-yl)oxy]pyrazine

[0033]2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(pyrrolidin-3-yl)oxy]pyrazine

[0034]2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(pyridin-4-yl)oxy]pyrazine.

[0035] In another aspect, the present invention provides a novelcompound of Formula I, or a stereoisomer thereof, a pharmaceuticallyacceptable salt thereof, or a prodrug thereof, which are useful for thetreatment of the disorders or diseases that are associated with CRF₁receptors, or disorders the treatment of which can be effected orfacilitated by antagonizing CRF, in a mammal, particularly in a human,such as social anxiety disorder; panic disorder; obsessive-compulsivedisorder; anxiety with co-morbid depressive illness; affective disorder;anxiety; and depression.

[0036] In still another aspect, the present invention provides for theuse of a compound of the invention for treatment of a disorder disclosedherein above in a mammal, particularly in a human.

[0037] In still another aspect, the present invention provides for acomposition comprising a compound of the invention useful for treatmentof a disorder disclosed herein above in a mammal, particularly in ahuman.

[0038] In still another aspect, the present invention provides for theuse of a compound of the invention in a binding assay, wherein one ormore of the compounds may be joined to a label, where the label candirectly or indirectly provide a detectable signal. Various labelsinclude radioisotopes, fluorescers, chemiluminescers, specific bindingmolecules, particles, e.g. magnetic particles, and the like.

[0039] In yet another aspect, the present invention relates to the useof the compounds of the invention (particularly labeled compounds ofthis invention) as probes for the localization of receptors in cells andtissues and as standards and reagents for use in determining thereceptor-binding characteristics of test compounds.

[0040] Labeled compounds of the invention may be used for in vitrostudies such as autoradiography of tissue sections or for in vivomethods, e.g. PET or SPECT scanning. Particularly, compounds of theinvention are useful as standards and reagents in determining theability of a potential pharmaceutical to bind to the CRF₁ receptor.

DETAILED DESCRIPTION OF THE INVENTION

[0041] In a first aspect, this invention provides a compound of FormulaI, shown and defined above.

[0042] Compounds provided herein can have one or more asymmetric centersor planes, and all chiral (enantiomeric and diastereomeric) and racemicforms of the compound are included in the present invention. Manygeometric isomers of olefins, C═N double bonds, and the like can also bepresent in the compounds, and all such stable isomers are contemplatedin the present invention. Compounds of the invention are isolated ineither the racemic form, or in the optically pure form, for example, byresolution of the racemic form by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example, a chiral HPLC column, or synthesized by anasymmetric synthesis route enabling the preparation of enantiomericallyenriched material. The present invention encompasses all possibletautomers of the compounds represented by Formula I.

[0043] Preferred compound of the invention include those of Formula II

[0044] or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, or a prodrug thereof, wherein in Formula II,

[0045] Ar is selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

[0046] m is 0,1 or 2;

[0047] R₁ and R₂ are independently selected from halogen, —NO₂, —CN,—R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a) —S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a);

[0048] R₃ and R₄ are independently selected from R_(a),heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl,substituted aryl, aryl cycloalkyl, substituted aryl cycloalkyl,heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, arylheterocycloalkyl, substituted aryl heterocycloalkyl, heteroarylheterocycloalkyl, or substituted heteroaryl heterocycloalkyl provided atleast one of R₃ or R₄ are heteroaryl, substituted heteroaryl, arylcycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl,substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substitutedaryl heterocycloalkyl, heteroaryl heterocycloalkyl, substitutedheteroaryl heterocycloalkyl, heterocycloalkyl or substitutedheterocycloalkyl;

[0049] R_(a) each is independently selected from H, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substitutedwith 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O),thione (═S), phenyl, heteroaryl, or heterocycloalkyl where phenyl,heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5independently taken from R_(t); and

[0050] R_(t) each is independently selected from H, halogen, —NO₂, —NH₂,—OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl,NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl,heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryl andheterocycloalkyl may be optionally substituted with alkyl or halogen.

[0051] Other preferred compounds of the invention include those ofFormula III

[0052] or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, or a prodrug thereof, wherein in Formula III,

[0053] Ar is selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

[0054] m is 0,1 or 2;

[0055] R₁ and R₂ are independently selected from halogen, —NO₂, —CN,—R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a) —S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a);

[0056] R₃ is selected from heteroaryl, substituted heteroaryl, arylcycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl,substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substitutedaryl heterocycloalkyl, heteroaryl heterocycloalkyl, substitutedheteroaryl heterocycloalkyl, heterocycloalkyl or substitutedheterocycloalkyl;

[0057] R_(a) each is independently selected from H, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substitutedwith 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O),thione (═S), phenyl, heteroaryl, or heterocycloalkyl where phenyl,heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5independently taken from R_(t); and

[0058] R_(t) each is independently selected from H, halogen, —NO₂, —NH₂,—OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl,NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl,heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryl andheterocycloalkyl may be optionally substituted with alkyl or halogen.

[0059] Still other preferred compounds of the invention include those ofFormula IV

[0060] or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, or a prodrug thereof, wherein in Formula IV,

[0061] Ar is selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

[0062] m is 0,1 or 2;

[0063] R₁ and R₂ are independently selected from halogen, —NO₂, —CN,—R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a) —S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a);

[0064] R_(s) each is independently selected from halogen, —NO₂, —CN,—R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a);

[0065] R_(a) each is independently selected from H, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substitutedwith 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O),thione (═S), phenyl, heteroaryl, or heterocycloalkyl where phenyl,heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5independently taken from R_(t); and

[0066] R_(t) each is independently selected from H, halogen, —NO₂, —NH₂,—OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl,NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl,heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryl andheterocycloalkyl may be optionally substituted with alkyl or halogen.

[0067] Still other preferred compounds of the invention include those ofFormula V

[0068] or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, or a prodrug thereof, wherein in Formula V,

[0069] Ar is selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

[0070] m is 0,01 or 2;

[0071] R_(s) each is independently selected from halogen, —NO₂, —CN,—R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a);

[0072] R_(a) each is independently selected from H, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substitutedwith 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O),thione (═S), phenyl, heteroaryl, or heterocycloalkyl where phenyl,heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5independently taken from R_(t); and

[0073] R_(t) each is independently selected from H, halogen, —NO₂, —NH₂,—OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl,NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl,heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryl andheterocycloalkyl may be optionally substituted with alkyl or halogen.

[0074] Still other preferred compounds of the invention include those ofFormula VI

[0075] or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, or a prodrug thereof, wherein in Formula VI,

[0076] Ar is selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

[0077] m is 0,1 or 2;

[0078] R_(s) each is independently selected from halogen, —NO₂, —CN,—R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a);

[0079] R_(a) each is independently selected from H, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substitutedwith 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O),thione (═S), phenyl, heteroaryl, or heterocycloalkyl where phenyl,heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5independently taken from R_(t);

[0080] R_(m) is C₁-C₆ alkyl substituted with from 1-2 of halogen, —NO₂,—NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl,NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, oxo (═O), thione (═S), heterocycloalkyl, or substitutedheterocycloalkyl; and

[0081] R_(t) each is independently selected from H, halogen, —NO₂, —NH₂,—OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl,NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl,heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryl andheterocycloalkyl may be optionally substituted with alkyl or halogen.

[0082] Still other preferred compounds of the invention include those ofFormula VII

[0083] or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, or a prodrug thereof, wherein in Formula VII,

[0084] Ar is selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

[0085] W is O, NR_(p), or S(O)_(m);

[0086] m is 0,1 or 2;

[0087] R_(s) each is independently selected from halogen, —NO₂, —CN,—R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a);

[0088] R₁ and R₂ are independently selected from halogen, —NO₂, —CN,—R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a), 13NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a);

[0089] R_(p) each is independently selected from —R_(a), —S(O)_(m)R_(a),—C(O)NR_(a)R_(a), —C(S)NR_(a)R_(a) —S(O)_(m)NR_(a)R_(a), —C(O)OR_(a), or—C(S)OR_(a);

[0090] R_(a) each is independently selected from H, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substitutedwith 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O),thione (═S), phenyl, heteroaryl, or heterocycloalkyl where phenyl,heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5independently taken from R_(t); and

[0091] R_(t) each is independently selected from H, halogen, —NO₂, —NH₂,—OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl,NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl,heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryl andheterocycloalkyl may be optionally substituted with alkyl or halogen.

[0092] Still other preferred compounds of the invention include those ofFormula VIII

[0093] or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, or a prodrug thereof, wherein in Formula VIII,

[0094] Ar is selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

[0095] W is O, NR_(p), or S(O)_(m);

[0096] m is 0,01 or 2;

[0097] R_(s) each is independently selected from halogen, —NO₂, —CN,—R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a);

[0098] R_(p) is independently selected from —R_(a), —S(O)_(m)R_(a),—C(O)NR_(a)R_(a), —C(S)NR_(a)R_(a) —S(O)_(m)NR_(a)R_(a), —C(O)OR_(a), or—C(S)OR_(a);

[0099] R_(a) each is independently selected from H, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substitutedwith 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O),thione (═S), phenyl, heteroaryl, or heterocycloalkyl where phenyl,heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5independently taken from R_(t); and

[0100] R_(t) each is independently selected from H, halogen, —NO₂, —NH₂,—OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl,NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl,heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryl andheterocycloalkyl may be optionally substituted with alkyl or halogen.

[0101] Still other preferred compounds of the invention include those ofFormula IX

[0102] or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, or a prodrug thereof, wherein in Formula IX,

[0103] Ar is selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

[0104] m is 0,1 or 2;

[0105] Y=O or S

[0106] R_(m) is C₁-C₆ alkyl substituted with from 1-2 of halogen, —NO₂,—NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl,NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, oxo (═O), thione (═S), heterocycloalkyl, or substitutedheterocycloalkyl;

[0107] R_(a) each is independently selected from H, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substitutedwith 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O),thione (═S), phenyl, heteroaryl, or heterocycloalkyl where phenyl,heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5independently taken from R_(t); and

[0108] R_(t) each is independently selected from H, halogen, —NO₂, —NH₂,—OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl,NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl, benzyl,heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryl andheterocycloalkyl may be optionally substituted with alkyl or halogen.

[0109] Still other preferred compounds of the invention include:

[0110] compounds of Formula I where X is NR3R4;

[0111] compounds of Formula I where X is NR3R4 and one of R3 or R4 isaryl cycloalkyl or heteroaryl cycloalkyl;

[0112] compounds of Formula I where X is NR3R4 and one of R3 or R4 isaryl cycloalkyl or heteroaryl cycloalkyl and the point of attachment isthe cycloalkyl ring;

[0113] compounds of Formula I where X is NR3R4 and one of R3 or R4 isaryl cycloalkyl or heteroaryl cycloalkyl and the point of attachment isthe cycloalkyl ring and one of R3 or R4 is hydrogen;

[0114] compounds of Formula I where X is NR3R4 and one of R3 or R4 isheterocycloalkyl and one of R3 or R4 is hydrogen;

[0115] compounds of Formula I where X is NR3R4 and one of R3 or R4 issubstituted aryl cycloalkyl or substituted heteroaryl cycloalkyl and thepoint of attachment is the cycloalkyl ring and one of R3 or R4 ishydrogen;

[0116] compounds of Formula I where X is NR3R4 and one of R3 or R4 issubstituted aryl cycloalkyl or substituted heteroaryl cycloalkyl wherethe substituent is either alkyl or alkoxy and is on the cycloalkyl ringand the point of attachment is the cycloalkyl ring and one of R3 or R4is hydrogen;

[0117] compounds of Formula I where X is NR3R4 and one of R3 or R4 issubstituted heterocycloalkyl where the substituent is either alkyl oralkoxy and one of R3 or R4 is hydrogen;

[0118] compounds of Formula I where X is NR3R4 and one of R3 or R4 issubstituted heterocycloalkyl where the substituent is either alkyl oralkoxy and the absolute stereochemistry of these ring substituents areeither (R,R), (R,S), (S,R), or (S,S) and one of R3 or R4 is hydrogen;

[0119] compounds of Formula I where X is NR3R4 and one of R3 or R4 issubstituted aryl cycloalkyl or substituted heteroaryl cycloalkyl wherethe substituent is either alkyl or alkoxy and is on the cycloalkyl ringand the absolute stereochemistry of these ring substituents are either(R,R), (R,S), (S,R), or (S,S) and the point of attachment is thecycloalkyl ring and one of R3 or R4 is hydrogen;

[0120] compounds of Formula I where X is NR3R4 and R3 is2-substituted-1-indanyl and R4 is hydrogen;

[0121] compounds of Formula I where X is NR3R4 and R3 is2-alkoxy-1-indanyl and R4 is hydrogen;

[0122] compounds of Formula I where X is NR3R4 and R3 is2(S)-alkoxy-1(R)-indanyl and R4 is hydrogen;

[0123] compounds of Formula I where X is NR3R4 and R3 is4-substituted-3-pyrrolidinyl and R4 is hydrogen;

[0124] compounds of Formula I where X is NR3R4 and R3 is4-alkoxy-3-pyrrolidinyl and R4 is hydrogen; and

[0125] compounds of Formula I where X is NR3R4 and R3 is4(S)-alkoxy-3(R)-pyrrolidinyl-1-carboxylate and R4 is hydrogen.

[0126] Following are examples of particular compounds of the invention,with each compound being identified by both a chemical name and astructural formula immediately below the chemical name:

[0127]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0128]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0129]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0130]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0131]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0132]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0133]N-[(1R,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine

[0134]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(prop-2-ynyloxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0135] 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0136]N-[(1R,2S)-2-(allyloxy)-2,3-dihydro-1H-inden-1-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine

[0137]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0138]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-propoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0139]2-[((1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)oxy]ethanol

[0140](1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yldimethylcarbamate

[0141](1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate

[0142]5-(2-chloro-4-methoxyphenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0143]5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0144](1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate

[0145]N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine

[0146]3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine

[0147]5-(2,4-dimethoxyphenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0148]5-(2,4-dimethoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0149]5-[2-chloro-4-(dimethylamino)phenyl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0150]5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0151]5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0152]5-(2,4-dichlorophenyl)-N-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine

[0153]N-(2,3-dihydro-1H-inden-1-yl)-5-(4-methoxy-2-methylphenyl)-3,6-dimethylpyrazin-2-amine

[0154]5-(2,4-dichlorophenyl)-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0155]5-(4-methoxy-2-methylphenyl)-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0156]N-[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]isoquinolin-1-amine

[0157]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(3-ethyl-6-methylpyridin-2-yl)pyrazin-2-amine

[0158]5-(2,4-dichlorophenyl)-N-(4,6-dimethylpyridin-2-yl)-3,6-diethylpyrazin-2-amine

[0159]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine

[0160]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine

[0161]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(cis)-5-ethyl-4,5,6,7-tetrahydro-1-benzofuran-4-yl]pyrazin-2-amine

[0162]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(cis)-5-ethyl-4,5,6,7-tetrahydro-1-benzofuran-4-yl]pyrazin-2-amine

[0163]5-(2,4-dichlorophenyl)-N-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amine

[0164]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0165]2-(2,4-dichlorophenyl)-3,6-diethyl-5-(1,2,3,4-tetrahydronaphthalen-1-yloxy)pyrazine

[0166]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0167]5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0168]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0169]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0170] 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2R) and(1S,2S)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine

[0171] 5-(2,4-dichlorophenyl)-N-[(1R,2R) and(1S,2S)-2-ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-3,6-diethylpyrazin-2-amine

[0172]cis-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

[0173] (cis)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine

[0174]5-(2,4-dichlorophenyl)-N-[(cis)-2-ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-3,6-diethylpyrazin-2-amine

[0175]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine

[0176]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Cis-5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0177]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Trans-5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0178]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Cis-5-ethyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0179]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Trans-5-ethyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0180]5-(2,4-dichlorophenyl)-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine

[0181]5-(2-chloro-4-methylphenyl)-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine

[0182]N-(3,4-dihydro-2H-chromen-4-yl)-5-(2,4-dimethylphenyl)-3,6-diethylpyrazin-2-amine

[0183]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0184]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0185]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethylpyrazin-2-amine

[0186]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethylpyrazin-2-amine

[0187]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethylpyrazin-2-amine

[0188]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0189]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine

[0190]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(cis)-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0191]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine

[0192]N-[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0193]N-[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine

[0194]N-[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0195]N-[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0196](+/−)-5-(2,4-dichlorophenyl)-3,6-diethyl-N-[cis-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0197](+/−)-5-(2,4-dichlorophenyl)-3,6-diethyl-N-[trans-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0198] benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0199]5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0200]N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine

[0201]5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxy-1-propionylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0202] methyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0203]5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxy-1-(methylsulfonyl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0204] ethyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0205](cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-N,N-dimethylpyrrolidine-1-carboxamide

[0206](cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-N,N-dimethylpyrrolidine-1-carbothioamide

[0207] isopropyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0208](cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-N-methylpyrrolidine-1-carbothioamide

[0209]5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxy-1-(morpholin-4-ylcarbonyl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0210] 2-fluoroethyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0211] benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0212]5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0213] methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0214] benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0215]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine

[0216] methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

Preparation ofmethyl(3R,4S)-3-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0217]

[0218] methyl(3R,4S)-3-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino)-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0219] benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate

[0220] benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0221] benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0222]5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0223] methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0224]5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine

[0225] methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0226]trans-(+/−)-N-[4-ethoxytetrahydrofuran-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine

[0227]cis-(+/−)-N-[4-ethoxytetrahydrofuran-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine

[0228]cis-(+/−)-5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[4-methoxytetrahydrofuran-3-yl]pyrazin-2-amine

[0229]cis-(+/−)-5-(2-chloro-4-methoxyphenyl)-N-[4-ethoxytetrahydrofuran-3-yl]-3,6-diethylpyrazin-2-amine

[0230]cis-(+/−)-5-(2-chloro-4-methoxyphenyl)-N-[4-propoxytetrahydrofuran-3-yl]-3,6-diethylpyrazin-2-amine

[0231] 5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3S,4S)-4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine

[0232]5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3S,4S)-4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine

[0233](+/−)-5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[cis-4-(3-fluoropropoxy)tetrahydrofuran-3-yl]pyrazin-2-amine

[0234]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(1-propyl-1H-imidazol-2-yl)pyrazin-2-amine

[0235]3,6-dicyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0236]6-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-methylpyrazin-2-amine

[0237]3-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-methylpyrazin-2-amine

[0238]6-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethylpyrazin-2-amine

[0239]5-(2-chloro-4-methoxyphenyl)-6-cyclopropyl-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethylpyrazin-2-amine

[0240]6-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethylpyrazin-2-amine

[0241]3-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine

[0242]3-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine

[0243]5-(2-chloro-4-methoxyphenyl)-3-cyclopropyl-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine

[0244]5-(2-chloro-4-methoxyphenyl)-3-cyclopropyl-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine

[0245]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethyl-3-methylpyrazin-2-amine

[0246]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethyl-6-methylpyrazin-2-amine

[0247](1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N²-ethyl-2,3-dihydro-1H-indene-1,2-diamine

[0248]N-((1R,2R)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)acetamide

[0249](1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N²-(2-methoxyethyl)-2,3-dihydro-1H-indene-1,2-diamine

[0250]5-(2,4-dichlorophenyl)-N-[(1S,2R)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0251]5-(2,4-dichlorophenyl)-N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0252]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0253] methyl3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylate

[0254] methyl6-{[(1R,2S)-2-(acetyloxy)-2,3-dihydro-1H-inden-1-yl]amino}-3-(2,4-dichlorophenyl)-5-methoxypyrazine-2-carboxylate

[0255]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-methoxy-3-vinylpyrazin-2-amine

[0256] methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-propoxypyrrolidine-1-carboxylate

[0257] methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)pyrrolidine-1-carboxylate

[0258] methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)pyrrolidine-1-carboxylate

[0259] methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}4-propoxypyrrolidine-1-carboxylate

[0260] methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(propionyloxy)pyrrolidine-1-carboxylate

[0261] methyl(3S,4R)-3-(acetyloxy)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}pyrrolidine-1-carboxylate

[0262] methyl(3S,4R)-3-(acetyloxy)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}pyrrolidine-1-carboxylate

[0263] methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(propionyloxy)pyrrolidine-1-carboxylate

[0264] methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(propionylamino)pyrrolidine-1-carboxylate

[0265] methyl(3S,4R)-3-(acetylamino)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}pyrrolidine-1-carboxylate

[0266] methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(ethylamino)pyrrolidine-1-carboxylate

[0267] methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(propylamino)pyrrolidine-1-carboxylate

[0268] O-methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-2-fluoroethoxy)pyrrolidine-1-carbothioate

[0269] O-methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carbothioate

[0270] O-methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)pyrrolidine-1-carbothioate

[0271] ethyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0272] ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0273] pyridin-2-ylmethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0274] pyridin-3-ylmethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0275] pyridin-4-ylmethyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0276] 2-piperidin-1-ylethyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0277] 2-morpholin-4-ylethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0278] 2-morpholin-4-ylethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(propionyloxy)pyrrolidine-1-carboxylate

[0279] 2-(dimethylamino)ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)pyrrolidine-1-carboxylate

[0280] 2-pyrrolidin-1-ylethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)pyrrolidine-1-carboxylate

[0281] 2-(1H-imidazol-1-yl)ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0282] 2-(methylamino)ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0283] 2-aminoethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0284] 2-hydroxyethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0285] 2-methoxyethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0286] 2-(2-oxopyrrolidin-1-yl)ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0287] 2-(2-oxopyridin-1(2H)-yl)ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0288](3S,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidin-2-one

[0289](3S,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-1-methylpyrrolidin-2-one

[0290](3S,4S)-1-benzyl-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidin-2-one

[0291](3R,4R)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-3-(2-fluoroethoxy)pyrrolidin-2-one

[0292](3R,4R)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-3-(2-fluoroethoxy)-1-methylpyrrolidin-2-one

[0293](3R,4R)-1-benzyl-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-3-(2-fluoroethoxy)pyrrolidin-2-one

[0294]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(1-ethyl-1H-imidazol-2-yl)pyrazin-2-amine

[0295] ethyl(2S,3S)-3-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-2,3-dihydrofuro[2,3-b]pyridine-2-carboxylate

[0296](2S,3S)-N-[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]-2-(ethoxymethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-amine

[0297](2R,3S)-N-[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]-2-ethyl-2,3-dihydrofuro[2,3-b]pyridin-3-amine

[0298](2R,3S)-N-[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]-2-propyl-2,3-dihydrofuro[2,3-b]pyridin-3-amine

[0299]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]pyrazin-2-amine

[0300]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyrazin-2-amine

[0301]5-(2,4-dichlorophenyl)-N-[(2R)-2-(ethoxymethyl)pyrrolidin-1-yl]-3,6-diethylpyrazin-2-amine

[0302]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(2R)-2-(propoxymethyl)pyrrolidin-1-yl]pyrazin-2-amine

[0303]5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-{(2R)-2-[(2-fluoroethoxy)methyl]pyrrolidin-1-yl}pyrazin-2-amine

[0304]5-(2-chloro-4-methoxyphenyl)-N-[(2R)-2-(ethoxymethyl)pyrrolidin-1-yl]-3,6-diethylpyrazin-2-amine

[0305]5-(2-chloro-4-methoxyphenyl)-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]-3,6-bis(methoxymethyl)pyrazin-2-amine

[0306]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]-3,6-bis(methoxymethyl)pyrazin-2-amine

[0307] methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-bis(methoxymethyl)pyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0308] methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-bis(methoxymethyl)pyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0309]5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(3-fluoropropoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0310]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(3-fluoropropoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0311](1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylhydroxyacetate

[0312](1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylhydroxyacetate

[0313](1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylmethoxyacetate

[0314](1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylmethoxyacetate

[0315]N-[(1R,2S)-2-(2-aminoethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-amine

[0316]N-[(1R,2S)-2-(2-aminoethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine

[0317](1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylglycinate

[0318](1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylglycinate

[0319]5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-{(1R,2S)-2-[2-(methylamino)ethoxy]-2,3-dihydro-1H-inden-1-yl}pyrazin-2-amine

[0320]5-(2,4-dichlorophenyl)-3,6-diethyl-N-{(1R,2S)-2-[2-(methylamino)ethoxy]-2,3-dihydro-1H-inden-1-yl}pyrazin-2-amine

[0321](1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylN-methylglycinate

[0322](1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylN-methylglycinate

[0323]5-(2-chloro-4-methoxyphenyl)-N-{(1R,2S)-2-[2-(dimethylamino)ethoxy]-2,3-dihydro-1H-inden-1-yl}-3,6-diethylpyrazin-2-amine

[0324]5-(2,4-dichlorophenyl)-N-{(1R,2S)-2-[2-(dimethylamino)ethoxy]-2,3-dihydro-1H-inden-1-yl}-3,6-diethylpyrazin-2-amine

[0325](1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylN,N-dimethylglycinate

[0326](1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylN,N-dimethylglycinate

[0327]5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-{(1R,2S)-2-[2-(methylamino)ethoxy]-2,3-dihydro-1H-inden-1-yl}pyrazin-2-amine

[0328](1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylmethylcarbamate

[0329]5-(4-chloro-2-methoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0330]5-(3,5-dichloropyridin-2-yl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0331]5-(3-chloro-5-methoxypyridin-2-yl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0332](1R,2S)-1-{[5-(4-chloro-2-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate

[0333](1R,2S)-1-{[5-(3,5-dichloropyridin-2-yl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate

[0334](1R,2S)-1-{[5-(3-chloro-5-methoxypyridin-2-yl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate

[0335]5-(4-chloro-2-methoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(3-fluoropropoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0336](3R,4R)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ylacetate

[0337](3R,4R)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ylacetate

[0338](3R,4R)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ylpropionate

[0339](3R,4R)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ylpropionate

[0340]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(3R,4R)-4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine

[0341]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(3R,4R)-4-(3-fluoropropoxy)tetrahydrofuran-3-yl]pyrazin-2-amine

[0342](3S,4R)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)dihydrofuran-2(3H)-one

[0343](3S,4R)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxydihydrofuran-2(3H)-one

[0344](3R,4S)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-5-oxotetrahydrofuran-3-ylacetate

[0345](3R,4S)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-5-oxotetrahydrofuran-3-ylpropionate

[0346](3S,4R)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-propoxydihydrofuran-2(3H)-one

[0347](3S,4R)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)dihydrofuran-2(3H)-one

[0348](1R,2S)-N-[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]-N′-ethyl-2,3-dihydro-1H-indene-1,2-diamine

[0349]N-((1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)acetamide

[0350]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethoxypyrazin-2-amine

[0351]3-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-methoxypyrazin-2-amine

[0352]3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-ethylpyrazine-2-carboxamide

[0353]3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxamide

[0354]3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-(methylthio)pyrazine-2-carboxamide

[0355]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethyl-3-(methylthio)pyrazin-2-amine

[0356]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethyl-3-methoxypyrazin-2-amine

[0357]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethyl-6-methoxypyrazin-2-amine

[0358]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethyl-6-(methylthio)pyrazin-2-amine

[0359]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-bis(methylthio)pyrazin-2-amine

[0360]6-(2,4-dichlorophenyl)-3-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-ethylpyrazine-2-carboxamide

[0361]6-(2,4-dichlorophenyl)-3-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxamide

[0362]6-(2,4-dichlorophenyl)-3-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-(methylthio)pyrazine-2-carboxamide

[0363]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethyl-N′-methylpyrazine-2,3-diamine

[0364]6-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-N′,N″-dimethylpyrazine-2,3,5-triamine

[0365]3-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-5-ethyl-N′-methylpyrazine-2,6-diamine

[0366] Compounds of the invention can be prepared using the reactionsdepicted in the following charts or variations thereof known to thoseskilled in the art. As illustrated in Chart A, the aminopyrazine A-IIcan be prepared from the suitably functionalized chloropyrazine A-I (seeChart C) by reaction with the appropriate heterocyclic or carbocyclicamine in the presence of a transition metal catalyst (e.g. palladium(II)acetate or tris(dibenzylideneacetone)dipalladium(0)), base (e.g. sodiumor potassium tert-butoxide) in solvents such as but not limited totoluene, DMF, or dioxane. (for example see Buchwald, S. L. et al J. Org.Chem. 2000, 65, 1158.). A variety of heterocyclic and carbocyclic aminesare commercially available or can be synthesized by those skilled in theart. Halogenation of A-II can be accomplished by a number of methodswell-known to those skilled in the art utilizing reagents such asN-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine,iodine, pyridinium tribromide in solvents such as dichloromethane,acetic acid, DMF, etc, to give the halopyrazine A-III. Formation of theclaimed compounds I is accomplished by a transition metal catalyzedcoupling reaction A-III and an appropriate metalloaryl reagent such asaryl boronic acids (see for example Miyaura, N.; et al Chem. Rev. 1995,95, 2457), aryl stannanes (see for example Mitchell, T. N. Synthesis1992, 803), or aryl Grignards (see for example Miller, J. A. TetrahedronLett. 1998, 39, 7275). Alternatively, A-I can be coupled with a suitablemetalloaryl reagent as described above to provide the arylpyrazine A-IV.Oxidation of the sterically less hindered nitrogen can be effected byusing a variety of known oxidizing agents (eg, MCPBA, hydrogenperoxide), and the resulting N-oxide can be treated with phosphorousoxybromide to provide the bromopyrazine A-V. Reaction of the halogenwith an amine as described above provides I.

[0367] Another way of preparing the compounds of this invention isillustrated in Chart B. Dialkyl-dichloropyrazines B-I (see Chart C) canserve as the starting point for sequential displacement of one chlorinewith the appropriate secondary amine (as described in Chart A) followedby biaryl formation with a suitable metalloaryl reagent (as described inChart A) to afford I. In some instances, this sequence can also beconducted in the opposite order, i.e. biaryl formation followed bynucleophilic displacement by a secondary amine.

[0368] Chart C illustrates the preparation of mono- and dichloropyrazineA-I and B-I respectively when R1 and R2 are alkyl and the same. Thereaction sequence shown below follows that described in Chemical andPharmaceutical Bulletin of Japan, 1979, 27, 2027.

[0369] As illustrated in Chart D, treatment of A-V (depicted in Chart A)with an alkoxide or sodium or potassium salt of a thiol should affordcompounds such as D-1. Alternatively, if direct alkoxide addition fails,palladium catalysis (see Buchwald, S. L. et al J. Am. Chem. Soc.2001,123, 10770) or copper catalysis (see Fagan, P. J. et al J. Am.Chem. Soc. 2000, 122, 5043) of an alkoxide will provide the desiredpyrazinyl aryl ether. Another literature method for forming aryl sulfurbonds is demonstrated by the work of Herradura et al. (see, Herradura,P. S. et al Org. Lett. 2000, 2, 2019).

[0370] As illustrated in Chart E, treatment of A-V (depicted in Chart A)with a nucleophile such as an alkyl Grignard or alkyl lithium reagentwould afford compounds such as E-I. Alternatively, treatment with analkyl boronic acid (see Fu, G. C. et al J. Am. Chem. Soc. 2000, 122,4020.) under transition metal catalysis should also provide compoundslike E-I.

[0371] As illustrated in Chart F, reaction of an amine with a pyrazinylchloride following the protocol of Buchwald et al (J. Org. Chem. 2000,1158.) provides the desired aniline (F-I). Halogenation with NBS (orother suitable reagents as described above) and standard palladiummediated coupling provides the biaryl product (F-III). Alkylation with abase such as NaH and an alkyl halide affords the desired alkyl ethers(F-IV).

[0372] The preparation of unsymmetrically substituted pyrazines (R₁≠R₂)is shown in Chart G. The synthesis commences with the coupling of asuitably protected amino acid, such as G-I, to an N-protected aminoacid, such as G-II, using methods known to those skilled in the art. TheN-protecting group is removed from G-III to afford G-IV. Cyclization ofG-IV to G-V and the conversion of G-V into the regioisomericchloro-pyrazines G-VI and G-VII proceed through standard methods (seeChemical and Pharmaceutical Bulletin of Japan, 1979, 27, 2027).

[0373] Yet another method for preparing the compounds of the presentinvention is detailed in Chart H. Following literature precedence (J.Heterocyclic Chem. 1986, 23, 1465), compounds H-I and H-II may bereacted in a suitable solvent (e.g. DME) in the presence of a base, suchas NaH, to form H-III. Formation of the triflate compound H-IV from theketone H-III is achieved by standard methods such as reaction of H-IIIwith 2-[N,N-bis(trifluoromethylsulfonylamino]-5-chloropyridine andtriethylamine in methylene chloride. The coupling partner H-V may beprepared from A-V (from Chart A) using the methods described inBuckwald, S. L. et al Tetrahedron Lett. 1997, 38, 6367.Palladium-catalyzed coupling (see, for example, Tetrahedron Lett. 1997,38, 6363) of H-IV and H-V gives H-VI, which may be reduced by standardmethods, such as catalytic hydrogenation, to give H-VII.

[0374] As illustrated in Chart I, the epoxide I-1 is prepared bytreatment of the commercially available olefin (benzyl2,5-dihydro-1H-pyrrole-1-carboxylate) with MCPBA. The resultant epoxidecan be opened in an asymmetric fashion with azide following the protocolof Jacobsen et al (J. Org. Chem. 1997, 62, 4197) or in a racemic fashionby treatment with ammonium hydroxide. Conversion of the trans aminoalcohol to the cis follows the protocol of Jacobsen et al (J. Org. Chem.1997, 62, 4197). Reaction of the pyrrolidine amine with a pyrazinylchloride following the protocol of Buchwald et al (J. Org. Chem. 2000,1158.) provides the desired aniline. Halogenation with NBS and standardpalladium mediated coupling provides the biaryl product. Alkylation withNaH and an alkyl halide or acid chloride affords the desired alkylethers or esters. Removal of the CBZ group and treatment of the aminewith chloroformates provides carbamates. Alternatively treatment with anacid chloride results in the production of amides. Otherfunctionalization of the amine can be carried out by those skilled inthe art.

[0375] As illustrated in Chart J, the commercially available epoxide J-1is opened in a racemic fashion by treatment with ammonium hydroxide orin an asymmetric fashion with azide following the protocol of Jacobsenet al (J. Org. Chem. 1997, 62, 4197). Conversion of the trans aminoalcohol to the cis follows the protocol of Jacobsen et al (J. Org. Chem.1997, 62, 4197). Reaction of the tetrahydrofuran amine J-3 with apyrazinyl chloride following the protocol of Buchwald et al (J. Org.Chem. 2000, 1158.) provides the desired aniline J-4. Halogenation withNBS affords J-5 followed by standard palladium mediated couplingprovides the biaryl product J-6. Alkylation with NaH and an alkyl halideor acid chloride affords the desired alkyl ethers or esters J-7.

[0376] In a second aspect, the present invention provides apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of theinvention useful for the treatment of a disorder described herein abovein a mammal, particularly in a human.

[0377] In another aspect, the present invention provides a method ofantagonizing a CRF₁ receptor in a mammal, comprising administering tothe mammal a therapeutically effective amount of a compound of theinvention.

[0378] In another aspect, the present invention provides a method oftreating a disorder manifesting hypersecretion of CRF in a mammal,comprising administering to the animal a therapeutically effectiveamount of a compound of the invention.

[0379] In another aspect, the present invention provides a method forthe treatment of a disorder, the treatment of which can be effected orfacilitated by antagonizing CRF₁ receptor, in a mammal, comprisingadministering to the mammal a therapeutically effective of a compound ofthe invention.

[0380] In another aspect, the present invention provides a method oftreating anxiety or depression in a mammal, particularly in a human,comprising administering to the mammal or human a therapeuticallyeffective amount of a compound of the invention.

[0381] In another aspect, the present invention provides a method forscreening for ligands for CRF₁ receptors, which method comprises: a)carrying out a competitive binding assay with CRF₁ receptors, a compoundof the invention which is labelled with a detectable label, and acandidate ligand; and b) determining the ability of said candidateligand to displace said labelled compound.

[0382] In another aspect, the present invention provides a method fordetecting CRF receptors in tissue comprising: a) contacting a compoundof the invention which is labelled with a detectable label, with atissue, under conditions that permit binding of the compound to thetissue; and b) detecting the labelled compound bound to the tissue.

[0383] In another aspect, the present invention provides a method ofinhibiting the binding of CRF to a CRF₁ receptor, comprising contactinga compound of the invention with a solution comprising cells expressingthe CRF₁ receptor, wherein the compound is present in the solution at aconcentration sufficient to inhibit the binding of CRF to the CRF₁receptor.

[0384] In another aspect, the present invention provides an article ofmanufacture comprising: a) a packaging material; b) a compound of theinvention; and c) a label or package insert contained within saidpackaging material indicating that said compound is effective fortreating a pre-selected disorder described herein above.

[0385] Compounds of the invention are useful for treating variousdisorders in a mammal, particularly in a human, such as social anxietydisorder; panic disorder; obsessive-compulsive disorder; anxiety withco-morbid depressive illness; affective disorder; anxiety; depression;irritable bowel syndrome; post-traumatic stress disorder; supranuclearpalsy; immune suppression; gastrointestinal disease; anorexia nervosa orother feeding disorder; drug or alcohol withdrawal symptoms; substanceabuse disorder (e.g., nicotine, cocaine, ethanol, opiates, or otherdrugs); inflammatory disorder; fertility problems; disorders thetreatment of which can be effected or facilitated by antagonizing CRF,including but not limited to disorders induced or facilitated by CRF; adisorder selected from inflammatory disorders such as rheumatoidarthritis and osteoarthritis, pain, asthma, psoriasis and allergies;generalized anxiety disorder; panic, phobias, obsessive-compulsivedisorder; post-traumatic stress disorder; sleep disorders induced bystress; pain perception such as fibromyalgia; mood disorders such asdepression, including major depression, single episode depression,recurrent depression, child abuse induced depression, and postpartumdepression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome;stress-induced headache; cancer, human immunodeficiency virus (HIV)infections; neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and Huntington's disease; gastrointestinal diseasessuch as ulcers, irritable bowel syndrome, Crohn's disease, spasticcolon, diarrhea, and post operative ilius and colonic hypersensitivityassociated by psychopathological disturbances or stress; eatingdisorders such as anorexia and bulimia nervosa; hemorrhagic stress;stress-induced psychotic episodes; euthyroid sick syndrome; syndrome ofinappropriate antidiarrhetic hormone (ADH); obesity; infertility; headtraumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebralischemia such as cerebral hippocampal ischemia); excitotoxic neuronaldamage; epilepsy; cardiovascular and hear related disorders includinghypertension, tachycardia and congestive heart failure; stroke; immunedysfunctions including stress induced immune dysfunctions (e.g., stressinduced fevers, porcine stress syndrome, bovine shipping fever, equineparoxysmal fibrillation, and dysfunctions induced by confinement inchickens, sheering stress in sheep or human-animal interaction relatedstress in dogs); muscular spasms; urinary incontinence; senile dementiaof the Alzheimer's type; multiinfarct dementia; amyotrophic lateralsclerosis; chemical dependencies and addictions (e.g., dependences onalcohol, cocaine, heroin, benzodiazepines, or other drugs);osteoporosis; psychosocial dwarfism and hypoglycemia.

[0386] Thus, in another aspect, the present invention provides a methodof treating a disorder described herein above in a mammal, particularlyin a human, comprising administering to the mammal or human atherapeutically effective amount of a compound of the invention.

[0387] Particular disorders that can be treated by the method of theinvention preferably include the following: affective disorder; anxiety;depression; irritable bowel syndrome; post-traumatic stress disorder;supranuclear palsy; obsessive-compulsive disorder; anxiety withco-morbid depressive illness; Alzheimer's disease; gastrointestinaldisease; skin disorders (e.g., acne, psoriasis); anorexia nervosa;social anxiety disorder; bulimia nervosa or other feeding disorder; drug(e.g., dependencies on cocaine, heroin, benzodiazepines, nicotine orother drugs) or alcohol withdrawal symptoms; substance abuse disorder(e.g., nicotine, cocaine, ethanol, opiates, or other drugs);inflammatory disorder; disorders; the treatment of which can be effectedor facilitated by antagonizing CRF, including but not limited todisorders induced or facilitated by CRF; or a disorder selected frominflammatory disorders such as rheumatoid arthritis and osteoarthritis,pain, asthma, psoriasis and allergies; generalized anxiety disorder;panic disorder; phobias; obsessive-compulsive disorder; sleep disordersinduced by stress; pain perception such as fibromyalgia; mood disorderssuch as depression, including major depression, single episodedepression, recurrent depression, child abuse induced depression, andpostpartum depression; dysthymia; bipolar disorders; cyclothymia;fatigue syndrome; stress-induced headache; cancer; neurodegenerativediseases such as, Parkinson's disease and Huntington's disease;gastrointestinal diseases such as ulcers, Crohn's disease, spasticcolon, diarrhea, and post operative ilius and colonic hypersensitivityassociated by psychopathological disturbances or stress; stress-inducedpsychotic episodes; syndrome of inappropriate antidiarrhetic hormone(ADH); cardiovascular and hear related disorders including hypertension,tachycardia and congestive heart failure; stroke; senile dementia of theAlzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis.

[0388] Particular disorders that can be treated by the method of theinvention more preferably include the following: generalized anxietydisorder; social anxiety disorder; anxiety; obsessive-compulsivedisorder; anxiety with co-morbid depressive illness; panic disorder;mood disorders such as depression, including major depression, singleepisode depression, recurrent depression, child abuse induceddepression, and postpartum depression; bipolar disorders; post-traumaticstress disorder; substance abuse disorder (e.g., nicotine, cocaine,ethanol, opiates, or other drugs); inflammatory disorders such asrheumatoid arthritis and osteoarthritis; gastrointestinal diseases suchas irritable bowel syndrome, ulcers, Crohn's disease, spastic colon,diarrhea, and post operative ilius and colonic hypersensitivityassociated by psychopathological disturbances or stress; inflammatorydisorder; and skin disorders such as acne and psoriasis.

[0389] Particular disorders that can be treated by the method of theinvention even more preferably include the following: generalizedanxiety disorder; social anxiety disorder; anxiety; obsessive-compulsivedisorder; anxiety with co-morbid depressive illness; panic disorder;mood disorders such as depression, including major depression, singleepisode depression, recurrent depression, child abuse induceddepression, and postpartum depression; bipolar disorders; andpost-traumatic stress disorder.

[0390] A compound of this invention can be administered to treat theseabnormalities in a mammal or human by means that produce contact of theactive agent with the agent's site of action in the body of the mammalor human. The compounds can be administered by any conventional meansavailable for use in conjunction with pharmaceuticals either asindividual therapeutic agent or in combination of therapeutic agents. Itcan be administered alone, but will generally be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

[0391] The dosage administered will vary depending on the use and knownfactors such as pharmacodynamic character of the particular agent, andits mode and route of administration; the recipient's age, weight, andhealth; nature and extent of symptoms; kind of concurrent treatment;frequency of treatment; and desired effect.

[0392] For use in the treatment of said diseases or conditions, acompound of this invention can be orally administered at a dosage of theactive ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, adose of 0.01 to 10 mg/kg in divided doses one to four times a day, or insustained release formulation will be effective in obtaining the desiredpharmacological effect.

[0393] Dosage forms (compositions) suitable for administration containfrom about 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions, the active ingredient will ordinarily bepresent in an amount of about 0.5 to 95% by weight based on the totalweight of the composition.

[0394] The active ingredient can be administered orally in solid dosageforms, such as capsules, tablets and powders; or in liquid forms such aselixirs, syrups, and/or suspensions. The compounds of this invention canalso be administered parenterally in sterile liquid dose formulations.Gelatin capsules can be used to contain the active ingredient and asuitable carrier such as but not limited to lactose, starch, magnesiumstearate, steric acid, or cellulose derivatives. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of time. Compressed tablets can besugar coated or film-coated to mask any unpleasant taste, or used toprotect the active ingredients from the atmosphere, or to allowselective disintegration of the tablet in the gastrointestinal tract.Liquid dose forms for oral administration can contain coloring orflavoring agents to increase patient acceptance. In general, water,pharmaceutically acceptable oils, saline, aqueous dextrose (glucose),and related sugar solutions and glycols, such as propylene glycol orpolyethylene glycol, are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, butter substances. Antioxidizing agents, such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or incombination, are suitable stabilizing agents. Also used are citric acidand its salts, and EDTA. In addition, parenteral solutions can containpreservatives such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol. Suitable pharmaceutical carriers are described in“Remington's Pharmaceutical Sciences”, A. Osol, a standard reference inthe field.

[0395] Useful pharmaceutical dosage forms or administration of thecompounds of this invention can be illustrated as follows: (1) Capsules.A large number of units capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 mg of powdered activeingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesiumstearate. (2) Soft Gelatin Capsules. A mixture of active ingredient in adigestible oil such as soybean, cottonseed oil, or olive oil is preparedand injected by means of a positive displacement was pumped into gelatinto form soft gelatin capsules containing 100 mg of the activeingredient. The capsules were washed and dried. (3) Tablets. A largenumber of tablets are prepared by conventional procedures so that thedosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicondioxide, 5 mg of magnesium stearate, 275 mg of microcrystallinecellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatingsmay be applied to increase palatability or delayed adsorption.

[0396] The compounds of this invention may also be used as reagents orstandards in the biochemical study of neurological function,dysfunction, and disease.

Definitions and Conventions

[0397] The term “substituted aryl” means an aryl group optionallysubstituted with 1-5 substituents independently selected from halogen,—NO₂, —CN, —R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a),—C(O)NR_(a)R_(a), —C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a),—NR_(a)S(O)_(m)R_(a), —NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a),—NR_(a)C(O)NR_(a)R_(a), —NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a),—C(S)OR_(a), and —OC(O)ORa;

[0398] The term “aryl cycloalkyl” means a bicyclic ring systemcontaining 8 to 14 carbon atoms wherein one ring is aryl and the otherring is fused to the aryl ring and may be fully or partially saturatedin the portion of the ring fused to the aryl ring, provided that eitherring may act as a point of attachment;

[0399] The term “substituted aryl cycloalkyl” means an aryl cycloalkylgroup having 1-5 substituents independently selected from halogen, —NO₂,—CN, —R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), and —OC(O)OR_(a);

[0400] The term “heteroaryl cycloalkyl” means a bicyclic ring systemcontaining 8 to 14 atoms, wherein one ring is heteroaryl and the otherring is fused to the heteroaryl ring and may be fully or partiallysaturated in the portion of the ring fused to the heteroaryl ring,provided that either ring may act as a point of attachment;

[0401] The term “substituted heteroaryl cycloalkyl” means a heteroarylcycloalkyl group having 1-5 substituents independently selected fromhalogen, —NO₂, —CN, —R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a),—C(O)NR_(a)R_(a), —C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a),—NR_(a)S(O)_(m)R_(a), —NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a),—NR_(a)C(O)NR_(a)R_(a), —NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a),—C(S)OR_(a), and —OC(O)OR_(a);

[0402] The term “aryl heterocycloalkyl” means a bicyclic ring systemcontaining 8 to 14 atoms, wherein one ring is aryl and the other ring isheterocycloalkyl, provided that either ring may act as a point ofattachment;

[0403] The term “substituted aryl heterocycloalkyl” means an arylheterocycloalkyl group having 1-5 substituents independently selectedfrom halogen, —NO₂, —CN, —R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a),—C(O)NR_(a)R_(a), —C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a),—NR_(a)S(O)_(m)R_(a), —NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a),—NR_(a)C(O)NR_(a)R_(a), —NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a),—C(S)OR_(a), and —OC(O)OR_(a);

[0404] The term “heteroaryl heterocycloalkyl” means a bicyclic ringsystem containing 8 to 14 atoms, wherein one ring is heteroaryl and theother ring is heterocycloalkyl, provided that either ring may act as apoint of attachment;

[0405] The term “substituted heteroaryl heterocycloalkyl” means anheteroaryl heterocycloalkyl group having 1-5 substituents independentlyselected from halogen, —NO₂, —CN, —R_(a), —OR_(a), —S(O)_(m)R_(a),—NR_(a)R_(a), —C(O)NR_(a)R_(a), —C(S)NR_(a)R_(a), —S(O)_(m)NR_(a)R_(a),—NR_(a)S(O)_(m)R_(a), —NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a),—NR_(a)C(O)NR_(a)R_(a), —NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a),—C(S)OR_(a), and —OC(O)OR_(a);

[0406] The term “heteroaryl” means a radical attached via a ring carbonor nitrogen atom of a monocyclic aromatic ring containing five or sixring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms eachselected from the group consisting of non-peroxide O, S, N, withappropriate bonding to satisfy valence requirements as well as a radical(attachment at either carbon or nitrogen) of a fused bicyclicheteroaromatic of about eight to ten ring atoms, and includes radicalssuch as thienyl, benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl,pyrimidyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,isothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl,and benzoxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl,oxazolyl, pyrrolyl, isoquinolinyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pydridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,quinazolinyl, quinoxalinyl, naphthridinyl, and furopyridinyl;

[0407] The term “substituted heteroaryl” means a heteroaryl group having1-5 substituents independently selected from halogen, —NO₂, —CN, —R_(a),—OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), and —OC(O)OR_(a)

[0408] The term “heterocycloalkyl”, unless otherwise specified, means a4 to 8 membered monocyclic ring or bicyclic ring, wherein at least onecarbon atom is replaced with a heteromember selected from oxygen,nitrogen, —NH—, or —S(O)_(m)— wherein m is zero, 1, or 2, optionallycontaining from one to three double bonds, provided that the molecule isnot aromatic; and provided that ring attachment can occur at either acarbon or nitrogen atom; Heterocycloalkyl includes tetrahydrofuranyl,tetrahydropyranyl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl,[2.2.1]-azabicyclic rings, [2.2.2]-azabicyclic rings,[3.3.1]-azabicyclic rings, quinuclidinyl, azetidinyl, azetidinonyl,oxindolyl, dihydroimidazolyl, and pyrrolidinonyl

[0409] The term “substituted heterocycloalkyl” is a heterocycloalkylgroup having 1-5 substituents independently selected from halogen, —NO₂,—CN, —R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), and —OC(O)OR_(a);

[0410] Halogen is a group selected from —F, —Cl, —Br, and —I;

[0411] The term “alkyl” means both straight and branched chain moietieshaving from 1-10 carbon atoms optionally containing one or more doubleor triple bonds;

[0412] The term “cycloalkyl” means a monocyclic or bicyclic alkylmoiety, having from 3-10 carbon atoms optionally containing 1 to 2double bonds provided that the moiety is not aromatic;

[0413] The term “haloalkyl” means an alkyl moiety having from 1-10carbon atoms and having 1 to (2v+1) independently selected halogensubstituent(s) where v is the number of carbon atoms in the moiety;

[0414] The term “pharmaceutically acceptable salt” refers to a saltprepared from pharmaceutically acceptable non-toxic acids, includinginorganic acids and organic acids. Suitable non-toxic acids includeinorganic and organic acids of basic residues such as amines, forexample, acetic, benzenesulfonic, benzoic, amphorsulfonic, citric,ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, barbaricacid, p-toluenesulfonic and the like; and alkali or organic salts ofacidic residues such as carboxylic acids, for example, alkali andalkaline earth metal salts derived from the following bases: sodiumhydride, sodium hydroxide, potassium hydroxide, calcium hydroxide,aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinchydroxide, ammonia, trimethylammonia, triethylammonia, ethylenediamine,lysine, arginine, ornithine, choline,N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine,n-benzylphenethylamine, diethylamine, piperazine,tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and thelike. Pharmaceutically acceptable salts of the compounds of theinvention can be prepared by reacting the free acid or base forms ofthese compounds with a stoichiometric amount of the appropriate base oracid in water or in an organic solvent, or in a mixture of the two;generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of suitable salts arefound in Remin ton's Pharmaceutical Sciences, 17th ea., Mack PublishingCompany, Easton, Pa, 1985, p. 1418, the disclosure of which is herebyincorporated by reference.

[0415] The term “prodrug” as used herein means any covalently bondedcarrier which releases the active parent drug of Formula I in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of thecompounds of Formula I are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” means compoundsthat are rapidly transformed in viva to yield the parent compound offormula I, for example by hydrolysis in blood. Functional groups whichmay be rapidly transformed, by metabolic cleavage, in viva form a classof groups reactive with the carboxyl group of the compounds of thisinvention. They include, but are not limited to such groups as alkanoyl(such as acetyl, propionyl, butyryl, and the like), unsubstituted andsubstituted aroyl (such as benzoyl and substituted benzoyl),alkoxycarbonyl (such as ethoxycarbonyl), trialkylsilyl (such astrimethyl- and triethysilyl), monoesters formed with dicarboxylic acids(such as succinyl), and the like. Because of the ease with which themetabolically cleavable groups of the compounds useful according to thisinvention are cleaved in viva, the compounds bearing such groups act aspro-drugs. The compounds bearing the metabolically cleavable groups havethe advantage that they may exhibit improved bioavailability as a resultof enhanced solubility and/or rate of absorption conferred upon theparent compound by virtue of the presence of the metabolically cleavablegroup. A thorough discussion of prodrugs is provided in the following:Design of Prodrugs, H. Bundgaard, ea., Elsevier, 1985; Methods inEnzymology, K. Widder et al, Ed., Academic Press, 42, p.309-396, 251985; A Textbook of Drug Design and Development, Krogsgaard-Larsen andH. Bundgaard, ea., Chapter 5; “Design and Applications of Prodrugs”p.113-191, 1991; Advanced Drug Delivery Reviews, H. Bundgard, 8, p.1-38,1992; Journal of Pharmaceutical Sciences, 77, p. 285, 30 1988; Chem.Pharm. Bull., N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as NovelDelivery Systems, T. Higuchi and V. Stella, Vol. 14 of the A.C.S.Symposium Series, and Bioreversible Carriers in Drug Design, Edward B.Roche, ea., American Pharmaceutical Association and Pergamon Press,1987, which are incorporated herein by reference. “Prodrugs” areconsidered to be any covalently bonded carriers which release the activeparent drug of Formula I in vivo when such prodrug is administered to amammalian subject. Prodrugs of the compounds of Formula I are preparedby modifying functional groups present in the compounds in such a waythat the modifications are cleaved, either in routine manipulation or invivo, to the parent compounds.

[0416] Prodrugs include compounds wherein hydroxy, amine, or sulthydrylgroups are bonded to any group that, when administered to a mammaliansubject, cleaves to form a free hydroxyl, amino, or sulfhydryl group,respectively. Examples of Prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of Formula I, and the like.

[0417] The term “therapeutically effective amount” of a compound of thisinvention means an amount effective to antagonize abnormal level of CRFor treat the symptoms of affective disorder, anxiety, depression, orother disorders described herein above, in a host.

[0418] The term “compound of the invention” means a compound of FormulaI, a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a prodrug thereof.

PREPARATIONS AND EXAMPLES

[0419] The invention is illustrated further by the following examplesand preparations, which are not to be construed as limiting theinvention in scope or spirit to the specific procedures described inthem.

Example A

[0420] CRF₁ Receptor Binding Assay for the Evaluation of BiologicalActivity

[0421] The following is a description of the isolation of rat brainmembranes for use in the standard binding assay as well as a descriptionof the binding assay itself. It is based on a modified protocoldescribed by De Souza (De Souza, 1987).

[0422] To prepare brain membranes for binding assays, rat frontal cortexis homogenized in 10 mL of ice cold tissue buffer (50 mM HEPES buffer pH7.0, containing 10 mM MgCl₂, 2 mM EGTA, 1 μg/ml aprotinin, 1 μg/mlleupeptin and 1 μg/ml pepstatin). The homogenate is centrifuged at48,000×g for 10 min. and the resulting pellet rehomogenized in 10 mL oftissue buffer. Following an additional centrifugation at 48,000×g for 10min., the pellet is resuspended to a protein concentration of 300 μg/mL.

[0423] Binding assays are performed in 96 well plates at a final volumeof 300 μL. The assays are initiated by the addition of 150 μL membranesuspension to 150 μL of assay buffer containing ¹²⁵I-ovine-CRF (finalconcentration 150 pM) and various concentrations of inhibitors. Theassay buffer is the same as described above for membrane preparationwith the addition of 0.1% ovalbumin and 0.15 mM bacitracin. Radioligandbinding is terminated after 2 hours at room temperature by filtrationthrough Packard GF/C unifilter plates (presoaked with 0.3%polyethyleneimine) using a Packard cell harvester. Filters are washedthree times with ice cold phosphate buffered saline pH 7.0 containing0.01% Triton X-100. Filters are assessed for radioactivity in a PackardTopCount. Nonspecific binding is determined in the presence of excess(10 μM) α-helical CRF.

[0424] Alternatively, tissues and cells that naturally express CRFreceptors, such as IMR-32 human neuroblastoma cells (ATCC; Hogg et al.,1996), can be employed in binding assays analogous to those describedabove.

[0425] IC₅₀ values are calculated using standard methods known in theart, such as with the non-linear curve fitting program RS/1 (BBNSoftware Products Corp., Cambridge, Mass.). A compound is considered tobe active if it has an IC₅₀ value of less than about 10 micromolar (μM)for the inhibition of CRF₁ receptors. The binding affinity of thecompounds of Formula I expressed as IC₅₀ values generally ranges fromabout 0.5 nanomolar to about 10 micromolar. Preferred compounds ofFormula I exhibit IC₅₀ of 1 micromolar or less, more preferred compoundsof Formula I exhibit IC₅₀ of less than 100 nanomolar or less, still morepreferred compounds of Formula I exhibit IC₅₀ of less than 10 nanomolaror less.

Example B

[0426] Inhibition of CRF-Stimulated Adenylate Cyclase Activity

[0427] Inhibition of CRF-stimulated adenylate cyclase activity can beperformed as previously described [G. Battaglia et al., Synapse 1:572(1987)]. Briefly, assays are carried out at 37° C. for 10 min in 200 mLof buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂,0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/mLphosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine5′-triphosphate, 100 nM o-CRF, antagonist peptides (variousconcentrations) and 0.8 mg original wet weight tissue (approximately40-60 mg protein). Reactions are initiated by the addition of 1 mMATP/[³²P]ATP (approximately 2-4 mCi/tube) and terminated by the additionof 100 mL of 50 mM Tris-HCl, 45 mM ATP and 2% sodium dodecyl sulfate. Inorder to monitor the recovery of cAMP, 1 mL of [³H]cAMP (approximately40,000 dpm) is added to each tube prior to separation. The separation of[³²P]cAMP from [³²P]ATP is performed by sequential elution over Dowexand alumina columns.

[0428] Alternatively, adenylate cyclase activity can be assessed in a96-well format utilizing the Adenylyl Cyclase Activation FlashPlateAssay from NEN Life Sciences according to the protocols provided.Briefly, a fixed amount of radiolabeled cAMP is added to 96-well platesthat are precoated with anti-cyclic AMP antibody. Cells or tissues areadded and stimulated in the presence or absence of inhibitors. UnlabeledcAMP produced by the cells will displace the radiolabeled cAMP from theantibody. The bound radiolabeled cAMP produces a light signal that canbe detected using a microplate scintillation counter such as the PackardTopCount. Increasing amounts of unlabeled cAMP results in a decrease ofdetectable signal over a set incubation time (2-24 hours).

[0429] Preparation 1

[0430](1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[0431] A solution of 3-chloro-2,5-diethylpyrazine (171 mg, 1.0 mmol),(1R,2S)-(+)-cis-1-amino-2-indanol (298 mg, 2.0 mmol),tris(dibenzylideneacetone)dipalladium (0) (28 mg, 0.03 mmol), and2-(di-tertbutylphosphino)biphenyl (18 mg, 0.06 mmol) in toluene (2.0 mL)was purged with nitrogen and treated with sodium tertbutoxide (135 mg,1.4 mmol). The resulting brown suspension was heated to 100° C. for 2hours. At this time, the reaction was quenched with a saturated watersolution of NaHCO₃ and extracted twice with ethyl acetate (20 mL). Thecombined organics were washed with brine (15 mL), dried over MgSO₄,filtered, and concentrated to give a black solid. This material waspurified by biotage MPLC (40 g column, 25% ethyl acetate/heptane) toafford 184 mg (65%) of the title compound as a light purple solid. IR(diffuse reflectance) 3435, 3241, 2962, 2935, 2912, 2873, 1581, 1547,1500, 1453, 1184, 1163, 1047, 744, 733 cm⁻¹; OAMS supporting ions at:ESI+384.0; MS (CI) m/z 284 (MH⁺); HRMS (FAB) calcd for C₁₇H₂₁N₃O +H₁284.1763, found 284.1754. [α]²⁵ _(D)=12 (c 0.55, methylene chloride);Anal. Calcd for C₁₇H₂₁N₃O: C, 72.06; H, 7.47; N, 14.83. Found: C, 72.15;H, 7.53; N, 14.42.

[0432] Preparation 2

[0433](1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[0434] A solution of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(1.94 g, 6.8 mmol) in dichloromethane (35 mL) was purged with nitrogenand cooled to 0° C. This light purple/grey homogenous solution wastreated with a single portion of N-bromosuccinimide (1.34 g, 7.5 mmol)instantly becoming a lighter color. The reaction was warmed to roomtemperature for 15 minutes, transferred to a separatory funnel, dilutedwith 100 mL additional dichloromethane, washed twice with water (75 mL),and once with brine (75 mL). The organics were dried over MgSO₄,filtered, and concentrated to give a golden oil. This material waspurified by biotage MPLC (90 g column, 15% ethyl acetate/heptane) toafford 2.24 g (90%) of the title compound as a pale yellow solid. IR(diffuse reflectance) 3416, 3355, 2969, 2941, 1555, 1538, 1482, 1385,1378, 1295, 1285, 1200, 1181, 1043, 733 cm⁻¹; OAMS supporting ions at:ESI+361.9; MS (EI) m/z 361 (M⁺); [α]²⁵ _(D)=−35 (c 0.53, methylenechloride); Anal. Calcd for C₁₇H₂₀BrN₃O: C, 56.36; H, 5.56; N, 11.60.Found: C, 56.46; H, 5.59; N, 11.50.

[0435] Preparation 3

[0436](1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[0437] A solution of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(1.48 g, 4.12 mmol) and 2,4-dichlorophenyl boronic acid (858 mg, 4.5mmol) in benzene (41 mL) and 2M sodium carbonate (7 mL) was purged withnitrogen and treated with a single portion ofbistriphenylphosphinepalladium(II)chloride (287 mg, 0.41 mmol). Theresulting golden 2-phase solution was heated to 80° C. graduallydarkening in color. After 16 hours, the reaction was cooled to roomtemperature, transferred to a separatory funnel, and washed with water(50 mL). The aqueous layer was extracted twice with ethyl acetate (75mL) and the combined organics were washed once with brine (75 mL), driedover MgSO₄, filtered, and concentrated to give 2.36 g of a brown syrup.This material was purified by biotage MPLC (90 g column, 20% ethylacetate/heptane) to afford 1.25 g (71%) of the title compound as a tansolid. OAMS supporting ions at: ESI+428.0; HRMS (FAB) calcd forC₂₃H₂₃CL₂N₃O+H₁ 428.1296, found 428.1292.

Example 1

[0438] The Preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0439] A solution of sodium hydride (60% oil dispersion, 26 mg, 0.65mmol) was suspended in DMF (1.5 mL), purged with nitrogen, and treatedwith a single portion of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol(214 mg, 0.5 mmol) with copious gas evolution. The resultinggreen/golden solution was stirred for 5 minutes at room temperature andtreated with iodoethane (88 μL, 1.1 mmol). After 3 hours, the reactionwas poured into 20 mL 1:1 water/brine and extracted twice with ethylacetate (20 mL). The combined organics were washed once with brine,dried over MgSO₄, filtered, and concentrated to give 389 mg of a goldenoil. This material was purified by LC (18 g silica gel, 7% ethylacetate/heptane) to afford 157 mg (69%) of the title compound as a paleyellow syrup. IR (liq.) 3446, 2972, 2935, 2896, 2874, 1565, 1552, 1498,1470, 1391, 1206, 1184, 1101, 1091, 1080 cm⁻¹; OAMS supporting ions at:ESI+456.1; MS (EI) m/z 455 (M⁺); [α]²⁵ _(D)=−94 (c 0.38, methylenechloride); Anal. Calcd for C₂₅H₂₇Cl₂N₃O: C 65.79; H, 5.96; N, 9.21.Found: C, 66.06; H, 6.10; N, 9.17.

Example 2

[0440] The Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0441] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting iodomethane provided the title compound as colorlesssyrup. OAMS supporting ions at: ESI+442.0; MS (EI) m/z 441 (M⁺); HRMS(FAB) calcd for C₂₄H₂₅CL₂N₃O+H₁ 442.1453, found 442.1456.

Example 3

[0442] The Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0443] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting 2-iodopropane (20 equivalents iodide and sodium hydridewith portion-wise addition) provided the title compound as a lightyellow syrup. IR (liq.) 2971, 2935, 1564, 1552, 1497, 1471, 1392, 1379,1368, 1206, 1177, 1140, 1123, 1101, 1061 cm⁻¹; OAMS supporting ions at:ESI+470.2; MS (EI) m/z 469 (M⁺ ); HRMS (FAB) calcd for C₂₆H₂₉CL₂N₃O+H₁470.1766, found 470.1773. [α]²⁵ _(D)=−93 (c 0.33, methylene chloride);Anal. Calcd for C₂₆H₂₉Cl₂N₃O: C, 66.38; H, 6.21; N, 8.93. Found: C,66.53; H, 6.19; N, 8.89.

[0444] Preparation 4

[0445] Preparation of(1S,2R)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[0446] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting (1S,2R)-(−)-cis-1-amino-2-indanol and making non-criticalvariations provided the title compound as a light purple solid. MS(ESI+) for C₁₇H₂₁N₃O m/z 284.0 (M+H)⁺.

[0447] Preparation 5

[0448] Preparation of(1S,2R)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[0449] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting(1S,2R)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol andmaking non-critical variations provided the title compound as a paleyellow solid. MS (ESI+) for C₁₇H₂₀BrN₃O m/z 361.9 (M+H)⁺.

[0450] Preparation 6

[0451] Preparation of(1S,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol.

[0452] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting(1S,2R)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as a tansolid. IR (diffuse reflectance) 3439, 2964, 1568, 1551, 1500, 1469,1391, 1373, 1204, 1183, 1102, 1048, 819, 748, 741 cm⁻¹; OAMS supportingions at: ESI+427.9; MS (EI) m/z 427 (M⁺); HRMS (FAB) calcd forC₂₃H₂₃CL₂N₃O+H₁ 428.1296, found 428.1286. Anal. Calcd for C₂₃H₂₃Cl₂N₃O:C, 64.49; H, 5.41; N, 9.81. Found: C, 64.43; H, 5.54; N, 9.42.

Example 4

[0453] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0454] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1S,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland iodomethane and making non-critical variations provided the titlecompound as a colorless syrup. IR (liq.) 3447, 2972, 2934, 2907, 2877,1589, 1565, 1552, 1498, 1471, 1391, 1375, 1196, 1177, 1093 cm⁻¹; OAMSsupporting ions at: ESI+442.0; MS (EI) m/z 441 (M⁺); [α]²⁵ _(D)=55 (c0.51, methanol); Anal. Calcd for C₂₄H₂₅Cl₂N₃O: C, 65.16; H, 5.70; N,9.50. Found: C, 65.20; H, 5.63; N, 9.43.

[0455] Preparation 7

[0456] Preparation of(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl4-nitrobenzoate

[0457] A solution of(1S,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol(321 mg, 0.75 mmol), 4-nitrobenzoic acid (552 mg, 3.3 mmol), andtriphenylphosphine (964 mg, 3.7 mmol) in benzene (19 mL) was purged withnitrogen and cooled to 0° C. The resulting yellow suspension was treatedwith diethylazodicarboxylate (0.58 mL, 3.7 mmol) becoming lighter incolor with gradual warming to RT. After 18 hours, the volatiles wereremoved under reduced pressure with the resulting crude residue beingabsorbed on 6 g silica gel and purified by Biotage MPLC (40 g column,15% ethyl acetate/heptane) to afford the title compound as a lightyellow solid. IR (diffuse reflectance) 1725, 1568, 1550, 1527, 1498,1467, 1392, 1372, 1349, 1320, 1273, 1119, 1103, 836, 719 cm⁻¹; OAMSsupporting ions at: ESI+576.8; MS (CI) m/z 577 (MH⁺); HRMS (FAB) calcdfor C₃₀H₂₆CL₂N₄O₄ +H₁ 577.1409, found 577.1417.

[0458] Preparation 8

[0459] Preparation of(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol.

[0460] A solution of(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl4-nitrobenzoate (369 mg, 0.64 mmol) in methanol (3 mL) andtetrahydrofuran (6 mL) was treated with a 1M solution of lithiumhydroxide (5 mL, 5 mmol). After 16 hrs, the volatiles were removed underreduced pressure and the aqueous residue was diluted with 1M sodiumhydroxide (10 mL) and extracted twice with ethyl acetate (20 mL). Thecombined organics were washed once with brine (20 mL), dried over MgSO₄,filtered, and concentrated to give 302 mg of a yellow syrup. Thismaterial was purified by Biotage MPLC (40 g column, 20% ethylacetate/heptane) to afford 250 mg (91%) of the title compound as a whitesolid. IR (diffuse reflectance) 3325, 2976, 2936, 2900, 2876, 1571,1550, 1503, 1471, 1449, 1435, 1399, 861, 819, 753 cm⁻¹; OAMS supportingions at: ESI+427.9; MS (EI) m/z 427 (M⁺); [α]²⁵ _(D)=−108 (c 0.58,methylene chloride); Anal. Calcd for C₂₃H₂₃Cl₂N₃O: C, 64.49; H, 5.41; N,9.81; Cl, 16.55. Found: C, 64.27; H, 5.46; N, 9.58.

Examples 5 and 6

[0461] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amineand5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-N-methylpyrazin-2-amine

[0462] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol.and iodomethane and making non-critical variations provided the titlecompounds. Analytical data for5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;IR (diffuse reflectance) 2965, 1569, 1551, 1500, 1468, 1397, 1393, 1372,1203, 1189, 1106, 988, 838, 819, 748 cm⁻¹; OAMS supporting ions at:ESI+442.1; MS (EI) m/z 441 (M⁺); Anal. Calcd for C₂₄H₂₅Cl₂N₃O: C, 65.16;H, 5.70; N, 9.50; Cl, 16.03. Found: C, 65.14; H, 5.90; N, 9.32.Analytical data for5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-N-methylpyrazin-2-amine;OAMS supporting ions at: ESI+455.8; HRMS (FAB) calcd for C₂₅H₂₇CL₂N₃O+H₁456.1609, found 456.1601.

[0463] Preparation 9

[0464] Preparation of(1R,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl4-nitrobenzoate

[0465] Following the procedure for the preparation of(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl4-nitrobenzoate but substituting(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol andmaking non-critical variations provided the title compound as a yellowsolid. IR (diffuse reflectance) 1725, 1568, 1550, 1527, 1498, 1467,1392, 1372, 1349, 1320, 1273, 1119, 1103, 1014, 719 cm⁻¹; OAMSsupporting ions at: ESI+577.1; MS (CI) m/z 577 (MH⁺); HRMS (FAB) calcdfor C₃₀H₂₆CL₂N₄O₄+H₁ 577.1409, found 577.1393; [α]²⁵ _(D)=−118 (c 0.62,methylene chloride).

[0466] Preparation 10

[0467] Preparation of(1R,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[0468] Following the procedure for the preparation of(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting(1R,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl4-nitrobenzoate and making non-critical variations provided the titlecompound as an off-white solid. IR (diffuse reflectance) 3326, 2976,1572, 1550, 1503, 1472, 1449, 1435, 1399, 1358, 1198, 1074, 862, 819,753 cm⁻¹; OAMS supporting ions at: ESI+428.1; MS (EI) m/z 427 (M⁺); HRMS(FAB) calcd for C₂₃H₂₃CL₂N₃O+H₁ 428.1296, found 428.1295. [α]²⁵ _(D)=112(c 0.58, methylene chloride). Anal. Calcd for C₂₃H₂₃Cl₂N₃O: C, 64.49; H,5.41; N, 9.81. Found: C, 64.60; H, 5.34; N, 9.75.

Examples 7 and 8

[0469] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amineand5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-N-methylpyrazin-2-amine

[0470] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland iodomethane and making non-critical variations provided the titlecompounds. Analytical data for5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine:IR (diffuse reflectance) 3382, 2963, 2933, 1568, 1550, 1500, 1469, 1396,1371, 1203, 1189, 1105, 988, 838, 748 cm⁻¹; OAMS supporting ions at:ESI+441.1; MS (EI) m/z 441 (M⁺); HRMS (FAB) calcd for C₂₄H₂₅CL₂N₃O+H₁442.1453, found 442.1455. [α]²⁵ _(D)=−76 (c 0.64, methylene chloride).Analytical data for5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-N-methylpyrazin-2-amine:OAMS supporting ions at: ESI+456.1.

Example 9

[0471] Preparation ofN-[(1R,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine

[0472] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting (bromomethyl)cyclopropane and making non-criticalvariations provided the title compound as a yellow amorphous solid. IR(liq.) 3442, 2971, 2935, 2874, 1565, 1552, 1498, 1471, 1393, 1206, 1184,1101, 1077, 1021, 740 cm⁻¹; OAMS supporting ions at: ESI+481.8; MS (EI)m/z 481 (M⁺); HRMS (FAB) calcd for C₂₇H₂₉CL₂N₃O +H₁ 482.1766, found482.1775. [α]²⁵ _(D)=−65 (c 0.73, methylene chloride); Anal. Calcd forC₂₇H₂₉Cl₂N₃O: C, 67.22; H, 6.06; N, 8.71. Found: C, 67.15; H, 6.08; N,8.66.

Example 10

[0473] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(prop-2-ynyloxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0474] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting propargylbromide and making non-critical variationsprovided the title compound as a white solid. IR (diffuse reflectance)3451, 3293, 2964, 2932, 1563, 1493, 1469, 1390, 1204, 1184, 1087, 1076,820, 742, 646 cm⁻¹; OAMS supporting ions at: ESI+ 465.8; MS (EI) m/z 465(M⁺); HRMS (FAB) calcd for C₂₆H₂₅CL₂N₃O+H₁ 466.1453, found 466.1455.[α]²⁵ _(D)=−56 (c 0.83, methylene chloride). Anal. Calcd forC₂₆H₂₅Cl₂N₃O: C, 66.96; H, 5.40; N, 9.01. Found: C, 66.96; H, 5.49 N,8.93.

Example 11

[0475] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0476] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting 2-bromoethylmethylether and making non-criticalvariations provided the title compound as a light yellow syrup. IR(liq.) 3418, 2971, 2934, 2875, 1565, 1552, 1498, 1471, 1392, 1376, 1201,1183, 1132, 1100, 748 cm⁻¹; OAMS supporting ions at: ESI+485.8; MS (CI)m/z 486 (MH⁺); [α]²⁵ _(D)=−102 (c 0.57, methylene chloride); Anal. Calcdfor C₂₆H₂₉Cl₂N₃O₂: C, 64.20; H, 6.01; N, 8.64. Found: C, 63.92; H, 6.14;N, 8.53.

Example 12

[0477] Preparation ofN-[(1R,2S)-2-(allyloxy)-2,3-dihydro-1H-inden-1-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine

[0478] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting allybromide and making non-critical variations providedthe title compound as a light yellow semi-solid. IR (liq.) 3446, 2972,2935, 2874, 1565, 1552, 1497, 1471, 1392, 1206, 1181, 1101, 1087, 1078,744 cm⁻¹; OAMS supporting ions at: ESI+467.9; MS (EI) m/z 467 (M⁺);[α]²⁵ _(D)=−73 (c 0.79, methylene chloride); Anal. Calcd forC₂₆H₂₇Cl₂N₃O: C, 66.67; H, 5.81; N, 8.97. Found: C, 66.49; H, 5.87; N,8.91.

Example 13

[0479] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0480] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting 1-bromo-2-fluoroethane and making non-criticalvariations provided the title compound as a light yellow amorphoussolid. IR (diffuse reflectance) 2972, 2934, 1564, 1551, 1498, 1468,1392, 1377, 1206, 1182, 1123, 1102, 1046, 826, 750 cm⁻¹; OAMS supportingions at: ESI+473.9; MS (EI) m/z 473 (M⁺); [α]²⁵ _(D)=−87 (c 0.77,methylene chloride); Anal. Calcd for C₂₅H₂₆Cl₂FN₃O: C, 63.30; H, 5.52;N, 8.86. Found: C, 63.10; H, 5.60; N, 8.79.

Example 14

[0481] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-propoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0482] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting 1-iodopropane and making non-critical variationsprovided the title compound as a light yellow syrup. IR (liq.) 3446,2967, 2935, 2875, 1564, 1552, 1497, 1470, 1392, 1206, 1184, 1101, 1091,1082, 748 cm⁻¹; OAMS supporting ions at: ESI+469.9; MS (EI) m/z 469(M⁺); [α]²⁵ _(D)=−98 (c 0.91, methylene chloride); Anal. Calcd forC₂₆H₂₉Cl₂N₃O: C, 66.38; H, 6.21; N, 8.93. Found: C, 66.53; H, 6.15; N,9.05.

Example 15

[0483] Preparation of2-[((1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)oxy]ethanol

[0484] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting 2-(bromoethoxy)-tertbutyldimethylsilane and makingnon-critical variations providedN-[(1R,2S)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine.The crude product was treated with 5% hydrochloric acid in ethanol for18 hrs followed by removal of the volatiles under reduced pressure. Theresulting residue was basified with 1N sodium hydroxide and extractedtwice with ethyl acetate. The combined organics were washed once withbrine, dried over MgSO₄, filtered, and concentrated to give a tan syrup.This material was purified by Biotage MPLC (40 g column, 25% ethylacetate/heptane) to afford 67 mg of the title compound as a white solid.IR (diffuse reflectance) 2969, 2933, 1567, 1551, 1498, 1468, 1392, 1373,1206, 1182, 1101, 1079, 1061, 1046, 749 cm⁻¹; OAMS supporting ions at:ESI+472.2; MS (EI) m/z 471 (M⁺); HRMS (FAB) calcd for C₂₅H₂₇CL₂N₃O₂+H₁472.1558, found 472.1560. [α]²⁵ _(D)=−73 (c 0.50, methylene chloride);Anal. Calcd for C₂₅H₂₇Cl₂N₃O₂: C, 63.56; H, 5.76; N, 8.89. Found: C,63.23; H, 5.91; N, 8.75.

Example 16

[0485] Preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yldimethylcarbamate

[0486] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting dimethylcarbamylchloride and making non-criticalvariations provided the title compound as a white solid. IR (diffusereflectance) 3374, 2965, 1694, 1568, 1551, 1503, 1469, 1397, 1354, 1218,1205, 1182, 765, 759, 751 cm⁻¹; OAMS supporting ions at: ESI+499.1; MS(EI) m/z 498 (M⁺); HRMS (FAB) calcd for C₂₆H₂₈CL₂N₄O₂+H₁ 499.1667, found499.1684. [α]²⁵ _(D)=63 (c 0.71, methylene chloride); Anal. Calcd forC₂₆H₂₈Cl₂N₄O₂: C, 62.53; H, 5.65; N, 11.22. Found: C, 62.37; H, 5.74; N,11.09.

Example 17

[0487] Preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate

[0488] A solution of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol(214 mg, 0.5 mmol) and pyridine (44 μL, 0.55 mmol) in dichloromethane (5mL) was purged with nitrogen and cooled to 0° C. The light yellowhomogenous solution was treated with acetyl chloride (34 μL, 0.48 mmol)with no visible change. The reaction mixture was gradually warmed to RT.After 16 hrs, the volatiles were removed under reduced pressure and theresulting residue was absorbed on 4 g silica gel and purified by BiotageMPLC (40 g column, 15% ethyl acetate/heptane) to afford the titlecompound as an off-white solid. IR (diffuse reflectance) 2971, 2934,1743, 1568, 1550, 1498, 1467, 1393, 1372, 1238, 1207, 1177, 1101, 1036,751 cm⁻¹; OAMS supporting ions at: ESI+470.1; MS (EI) m/z 469 (M⁺); HRMS(FAB) calcd for C₂₅H₂₅CL₂N₃O₂+H₁ 470.1402, found 470.1404. [α]²⁵ _(D)=73(c 0.60, methylene chloride); Anal. Calcd for C₂₅H₂₅Cl₂N₃O₂: C, 63.83;H, 5.36; N, 8.93. Found: C, 63.45; H, 5.40; N, 8.79.

[0489] Preparation 11

[0490] Preparation of(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[0491] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting 2-chloro-4-methoxyphenylboronic acid and makingnon-critical variations provided the title compound as an off-whiteamorphous solid. IR (diffuse reflecture) 2969, 2934, 1604, 1568, 1550,1482, 1448, 1439, 1392, 1287, 1228, 1203, 1180, 1045, 740 cm⁻¹; OAMSsupporting ions at: ESI+423.9; MS (CI) m/z 424 (MH⁺); HRMS (FAB) calcdfor C₂₄H₂₆CLN₃O₂+H₁ 424.1792, found 424.1789. Anal. Calcd forC₂₄H₂₆ClN₃O₂: C, 68.00; H, 6.18; N, 9.91. Found: C, 67.86; H, 6.29; N,9.79.

Example 18

[0492] Preparation of5-(2-chloro-4-methoxyphenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0493] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as a paleyellow semi-solid. IR (liq.) 2971, 2935, 2875, 1606, 1565, 1480, 1440,1391, 1287, 1230, 1206, 1183, 1091, 1079, 1044 cm⁻¹; OAMS supportingions at: ESI+452.1; MS (EI) m/z 451 (M⁺); MS (FAB) calcd forC₂₆H₃₀CLN₃O₂ +H₁ 452.2104, found 452.2100. [α]²⁵ _(D)=−91 (c 0.39,methylene chloride); Anal. Calcd for C₂₆H₃₀ClN₃O₂: C, 69.09; H, 6.69; N,9.30. Found: C, 69.04; H, 6.74; N, 9.30.

Example 19

[0494] Preparation of5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0495] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland 1-bromo-2-fluoroethane and making non-critical variations providedthe title compound as a pale yellow semi-solid. IR (diffuse reflectance)2970, 1604, 1564, 1481, 1439, 1391, 1286, 1228, 1204, 1182, 1123, 1109,1044, 876, 750 cm⁻¹; OAMS supporting ions at: ESI+470.1; MS (EI) m/z 469(M⁺); HRMS (FAB) calcd for C₂₆H₂₉CLFN₃O₂+H₁ 470.2010, found 470.2013.[α]²⁵ _(D)=−82 (c 0.39, methylene chloride); Anal. Calcd forC₂₆H₂₉ClFN₃O₂: C, 66.45; H, 6.22; N, 8.94. Found: C, 66.41; H, 6.37; N,8.84.

Example 20

[0496] Preparation of(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate

[0497] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate but substituting(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as alight yellow semi-solid. IR (diffuse reflectance) 2969, 2933, 1742,1604, 1568, 1551, 1482, 1439, 1393, 1372, 1286, 1232, 1204, 1176, 1037cm⁻¹; OAMS supporting ions at: ESI+465.2; MS (EI) m/z 465 (M⁺); [α]²⁵_(D)=79 (c 0.80, methylene chloride); Anal. Calcd for C₂₆H₂₈ClN₃O₃: C,67.02; H, 6.06; N, 9.02. Found: C, 66.99; H, 6.18; N, 8.92.

[0498] Preparation 12

[0499] Preparation of(1R,2S)-1-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[0500] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting 2-methyl-4-methoxyphenylboronic acid and makingnon-critical variations provided the title compound as a peach coloredfoam. IR (diffuse reflectance) 3439, 2968, 2933, 2875, 1608, 1564, 1482,1391, 1294, 1279, 1242, 1204, 1175, 1050, 742 cm⁻¹; OAMS supporting ionsat: ESI+404.0 & ESI−402.1; MS (EI) m/z 403 (M⁺); HRMS (FAB) calcd forC₂₅H₂₉N₃O₂+H₁ 404.2338, found 404.2324. Anal. Calcd for C₂₅H₂₉N₃O₂: C,74.41; H, 7.24; N, 10.41. Found: C, 74.05; H, 7.44; N, 10.28.

Example 21

[0501] Preparation ofN-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine

[0502] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as alight yellow semi-solid. IR (liq.) 2971, 2934, 1609, 1562, 1480, 1391,1294, 1243, 1206, 1184, 1171, 1161, 1119, 1091, 1054 cm⁻¹; OAMSsupporting ions at: ESI+432.1; MS (EI) m/z 431 (M⁺); HRMS (FAB) calcdfor C₂₇H₃₃N₃O₂+H₁ 432.2651, found 432.2650. Anal. Calcd for C₂₇H₃₃N₃O₂:C, 75.14; H, 7.71; N, 9.74. Found: C, 74.86; H, 7.72; N, 9.67.

Example 22

[0503] Preparation of3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine

[0504] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland 1-bromo-2-fluoroethane and making non-critical variations providedthe title compound as a pale yellow semi-solid. IR (liq.) 2969, 2935,1609, 1563, 1482, 1391, 1294, 1243, 1206, 1182, 1172, 1159, 1124, 1110,1047 cm⁻¹; OAMS supporting ions at: ESI+450.0; MS (CI) m/z 450 (MH⁺);HRMS (FAB) calcd for C₂₇H₃₂FN₃O₂ +H₁ 450.2556, found 450.2544. Anal.Calcd for C₂₇H₃₂FN₃O₂: C, 72.14; H, 7.17; N, 9.35. Found: C, 72.24; H,7.20; N, 9.33.

[0505] Preparation 13

[0506] Preparation of(1R,2S)-1-{[5-(2,4-dimethoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[0507] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting 2,4-dimethoxyphenylboronic acid and making non-criticalvariations provided the title compound as an off-white foam. IR (diffusereflectance) 2966, 2934, 1610, 1567, 1483, 1391, 1303, 1280, 1253, 1208,1159, 1128, 1046, 1034, 741 cm⁻¹; OAMS supporting ions at: ESI+420.1; MS(EI) m/z 419 (M⁺); HRMS (FAB) calcd for C₂₅H₂₉N₃O₃+H₁ 420.2287, found420.2278.

Example 23

[0508] Preparation of5-(2,4-dimethoxyphenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0509] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2,4-dimethoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-1H-inden-2-oland making non-critical variations provided the title compound as awhite solid, m.p. 120-121° C. (uncorrected). IR (diffuse reflectance)2965, 2935, 1615, 1566, 1480, 1390, 1305, 1256, 1215, 1209, 1183, 1165,1040, 825, 747 cm⁻¹; OAMS supporting ions at: ESI+448.1; MS (EI) m/z 447(M⁺); HRMS (FAB) calcd for C₂₇H₃₃N₃O₃+H₁ 448.2600, found 448.2600. Anal.Calcd for C₂₇H₃₃N₃O₃: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.46; H,7.59; N, 9.39.

Example 24

[0510] Preparation of5-(2,4-dimethoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine.

[0511] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2,4-dimethoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland 1-bromo-2-fluoroethane and making non-critical variations providedthe title compound as a white solid. IR (diffuse reflectance) 2964,2935, 1614, 1567, 1480, 1392, 1305, 1256, 1215, 1209, 1165, 1158, 1040,825, 747 cm⁻¹; OAMS supporting ions at: ESI+466.2; MS (EI) m/z 465 (M⁺);Anal. Calcd for C₂₇H₃₂FN₃O₃: C, 69.66; H, 6.93; N, 9.03. Found: C,69.61; H, 7.02; N, 8.98.

[0512] Preparation 14

[0513] Preparation of(1R,2S)-1-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol

[0514] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting 2-chloro-4-dimethylaminophenylboronic acid and makingnon-critical variations provided the title compound as a pale yellowamorphous solid. IR (diffuse reflectance) 2969, 2932, 1607, 1567, 1550,1486, 1443, 1391, 1353, 1225, 1207, 1177, 1043, 961, 740 cm⁻¹; OAMSESI+437.2; MS (EI) m/z 436 (M⁺); HRMS (FAB) calcd for C₂₅H₂₉CLN₄O+H₁437.2108, found 437.2089. [α]²⁵ _(D)=−7 (c 0.70, methylene chloride);Anal. Calcd for C₂₅H₂₉ClN₄O: C, 68.72; H, 6.69; N, 12.82. Found: C,68.48; H, 6.84; N, 12.66.

Example 25

[0515] Preparation of5-[2-chloro-4-(dimethylamino)phenyl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0516] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as a paleyellow amorphous solid. IR (diffuse reflectance) 2971, 2932, 2890, 2875,1608, 1563, 1482, 1442, 1389, 1366, 1352, 1207, 1175, 1090, 961 cm⁻¹;OAMS supporting ions at: ESI+465.2; MS (EI) m/z 464 (M⁺); HRMS (FAB)calcd for C₂₇H₃₃CLN₄O+H₁ 465.2421, found 465.2406. Anal. Calcd forC₂₇H₃₃ClN₄O: C, 69.74; H, 7.15; N, 12.05. Found: C, 69.68; H, 7.16; N,11.99.

Example 26

[0517] Preparation of5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0518] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino2,3-dihydro-1H-inden-2-ol and 1-bromo-2-fluoroethane and makingnon-critical variations provided the title compound as a light yellowamorphous solid. IR (diffuse reflectance) 2969, 2932, 2907, 2877, 1608,1563, 1545, 1483, 1447, 1392, 1353, 1207, 1177, 1123, 1042 cm⁻¹; OAMSsupporting ions at: ESI+483.2; MS (EI) m/z 482 (M⁺); HRMS (FAB) calcdfor C₂₇H₃₂CLFN₄O+H₁ 483.2327, found 483.2324. [α]²⁵ _(D)=−79 (c 0.52,methylene chloride); Anal. Calcd for C₂₇H₃₂ClFN₄O: C, 67.14; H, 6.68; N,11.60. Found: C, 67.19; H, 6.90; N, 11.63.

Preparation 15

[0519] Preparation of(1R,2S)-1-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol

[0520] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting 6-(dimethylamino)-4-methylpyridin-3-ylboronic acid andmaking non-critical variations provided the title compound as a lightyellow amorphous solid. IR (diffuse reflectance) 3448, 2962, 2954, 2933,1611, 1567, 1520, 1482, 1392, 1376, 1174, 1160, 1046, 741, 737 cm⁻¹;OAMS supporting ions at: ESI+418.3; MS (EI) m/z 417 (M⁺); HRMS (FAB)calcd for C₂₅H₃₁N₅O+H₁ 418.2607, found 418.2611. Anal. Calcd forC₂₅H₃₁N₅O: C, 71.91; H, 7.48; N, 16.77. Found: C, 71.59; H, 7.57; N,16.40.

Example 27

[0521] Preparation of5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[0522] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as alight golden amorphous solid. IR (diffuse reflectance) 3446, 2969, 2931,2893, 2874, 1604, 1562, 1517, 1487, 1392, 1372, 1208, 1174, 1123, 1089cm⁻¹; OAMS supporting ions at: ESI+446.3; MS (EI) m/z 445 (M⁺); HRMS(FAB) calcd for C₂₇H₃₅N₅O+H₁ 446.2920, found 446.2915. [α]²⁵ _(D)=−89 (c0.47, methylene chloride); Anal. Calcd for C₂₇H₃₅N₅O: C, 72.78; H, 7.92;N, 15.72. Found: C, 72.58; H, 7.94; N, 15.59.

[0523] Preparation 16

[0524] Preparation ofN-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine

[0525] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 1-Aminoindane and 3-chloro-2,5-dimethylpyrazine, and makingnon-critical variations provided the title compound as a oil: ¹H NMR(CDCl₃) δ1.88, 2.35, 2.41, 2.77, 2.94, 3.03, 4.55, 5.78, 7.3, 7.64; MS(ESI+) for C₁₅H₁₇N₃ m/z 240.30 (M+H)⁺.

[0526] Preparation 17

[0527] Preparation of5-bromo-N-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine

[0528] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substitutingN-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(CDCl₃) δ1.86, 2.26, 2.53, 2.70, 2.93, 3.03, 4.50, 5.72, 7.28; ¹³C NMR(CDCl₃) δ19.23, 23.21, 30.25, 34.56, 56.45, 124.05, 124.81, 124.97,126.78, 128.03, 136.98, 143.71, 144.09, 148.36, 151.15; MS (ESI+) forC₁₅H₁₆N₃Br₁ m/z 319.20 (M+H)⁺.

Example 28

[0529] Preparation of5-(2,4-dichlorophenyl)-N-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine

[0530] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-N-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ1.94, 2.29, 2.39, 2.80, 2.96, 3.08, 4.64, 5.83, 7.33, 7.51;MS (ESI+) for C₂₁H₁₉Cl₂N₃ m/z 385.30 (M+H)⁺.

Example 29

[0531] Preparation ofN-(2,3-dihydro-1H-inden-1-yl)-5-(4-methoxy-2-methylphenyl)-3,6-dimethylpyrazin-2-amine

[0532] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-N-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine and2-methyl-4-methoxy phenyl boronic acid, and making non-criticalvariations provided the title compound as a oil: ¹H NMR (CDCl₃) δ1.92,2.17, 2.26, 2.39, 2.80, 2.98, 3.07, 3.85, 4.54, 5.82, 6.84, 7.15, 7.30,7.41; MS (ESI+) for C₂₃H₂₅N₃O₁ m/z 360.4 (M+H)⁺.

[0533] Preparation 18

[0534] Preparation of3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0535] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 1,2,3,4-tetrahydronaphthalen-1-amine and3-chloro-2,5-dimethylpyrazine, and making non-critical variationsprovided the title compound as a oil: ¹H NMR (CDCl₃) δ1.91, 2.11, 2.31,2.40, 2.87, 4.50, 5.16, 7.21, 7.35, 7.62; MS (ESI+) for C₁₆H₁₉N₃ m/z254.4 (M+H)⁺.

[0536] Preparation 19

[0537] Preparation of5-bromo-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0538] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ1.92, 2.08, 2.29, 2.53, 2.86, 4.48, 5.40, 7.21, 7.33; ¹³CNMR (CDCl₃) δ19.63, 20.32, 23.67, 29.81, 30.00, 49.20, 124.85, 126.66,127.69, 129.23, 129.63, 137.17, 138.12, 138.25, 148.78, 151.23; MS(ESI+) for C₁₆H₁₈N₃Br₁ m/z 333.3 (M+H)⁺.

Example 30

[0539] Preparation of5-(2,4-dichlorophenyl)-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0540] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting Preparation of5-bromo-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (CDCl₃) δ1.95, 2.15, 2.28, 2.35, 2.90, 4.62, 5.52, 7.23, 7.34,7.41, 7.51; MS (ESI+) for C₂₂H₂₁Cl₃N₃ m/z 399.1 (M+H)⁺.

Example 31

[0541] Preparation of5-(4-methoxy-2-methylphenyl)-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0542] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-(2,4-dichlorophenyl)-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amineand 2-methyl-4-methoxy phenyl boronic acid, and making non-criticalvariations provided the title compound as a oil: ¹H NMR (CDCl₃) δ1.81,2.01, 2.06, 2.13, 2.22, 2.77, 3.71, 4.38, 5.39, 6.70, 7.09, 7.31; ¹³CNMR (CDCl₃) δ20.07, 20.47, 20.54, 22.09, 29.96, 30.28, 48.94, 55.68,111.58, 116.05, 126.64, 127.57, 129.43, 129.60, 131.24, 132.37, 135.83,138.31, 138.56, 138.74, 140.69, 147.04, 150.92, 159.51; HRMS (ESI+) forC₂₄H₂₇N₃O₁ m/z cald 374.2232 (M+H)⁺ found 374.2226

[0543] Preparation 20

[0544] Preparation of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine

[0545] To a solution of 3-chloro-2,5-dimethylpyrazine (2 g, 14 mmol) inDME (35 ml) and 2N sodium bicarbonate (14 ml) was added2,4-dichloroboranic acid (15.4 mmol, 2.94 g) andtetrakis(triphenylphosphine)palladium (810 mg). The reaction mixture washeated at 85° C. for 12 hr. The reaction mixture was cooled, dilutedwith Et₂O, washed with NaHCO₃ (sat'd) and dried (MgSO₄). Flashchromatography (Silica gel, Heptane:EtOAc 20:1) gave the title compound(91% yield). ¹H NMR (CDCl₃) δ2.40, 2.60, 7.29, 7.40, 8.43; ¹³C NMR(CDCl₃) δ21.52, 21.72, 127.97, 129.99, 131.80, 134.18, 135.69, 136.77,143.58, 149.73, 150.66, 150.82; MS (ESI+) for C₁₂H₁₀Cl₂N₂ m/z 254.2(M+H)⁺.

[0546] Preparation 21

[0547] Preparation of2-bromo-5-(2,4-dichlorophenyl)-3,6-dimethylpyrazine

[0548] POBr3 (573 mg) was added to the solution of3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine 1-oxide (270 mg) and protonsponge (197 mg) in CH₂Cl₂ at 0° C. The reaction mixture was warmed tor.t. for 10 h. The reaction mixture was washed with 1N HCl, NaHCO₃ andbrine, dried (MgSO₄), filtered and concentrated. Flash chromatography(silica gel Heptane:EtOAC 100:1) gave the title compound (110 mg, 35%)and 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine (100 mg, 38%). ¹H NMR(CDCl₃) δ2.40, 2.71, 7.28, 7.40, 7.54; MS (ESI+) for C₁₂H₉Cl₂N₂Br₁ m/z333.0 (M+H)⁺.

Example 32

[0549] Preparation ofN-[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]isoquinolin-1-amine

[0550] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 2-bromo-5-(2,4-dichlorophenyl)-3,6-dimethylpyrazine andisoquinolin-1-amine, and making non-critical variations provided thetitle compound as a oil: ¹H NMR (CDCl₃) δ2.36, 2.93, 6.75, 7.38, 7.53,7.57, 8.96; HRMS (ESI+) calcd for C₂₁H₁₆Cl₂N₄ (M+H)⁺ 395.0830, found395.0821.

[0551] Preparation 22

[0552] Preparation of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine1-oxide

[0553] To a solution of 3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine at020 C. in dioxane was added mCPBA (750 mg). The reaction mixture washeated at 45° C. for 3 h. The reaction was diluted with CH₂Cl₂, washedwith NaHCO₃, dried (MgSO₄), filtered, and concentrated. It was usedwithout purification: ¹H NMR (CDCl₃) δ2.30, 2.54, 7.33, 7.42, 7.54,8.13; ¹³C NMR (CDCl₃) δ14.04, 21.85, 128.10, 130.12, 131.64, 132.14,134.07, 135.23, 136.44, 141.66, 153.87, 154.24.

[0554] Preparation 23

[0555] Preparation of 3-(2,4-dichlorophenyl)-2,5-diethylpyrazine

[0556] Following the procedure for the preparation of3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine but3-chloro-2,5-diethylpyrazine and making non-critical variations providedthe title compound as a oil: ¹H NMR (CDCl₃) δ1.19, 1.35, 2.65, 2.88,7.29, 7.39, 7.54, 8.47; ¹³C NMR (CDCl₃) δ13.52, 14.48, 28.03, 28.97,128.01, 130.22, 132.07, 134.61, 135.77, 137.02, 143.22, 150.44, 154.57,155.84; MS (ESI+) for C₁₄H₁₄Cl₂N₂ m/z 282.2 (M+H)⁺.

[0557] Preparation 24

[0558] Preparation of 3-(2,4-dichlorophenyl)-2,5-diethylpyrazine 1-oxide

[0559] Following the procedure of3-(2,4-dichlorophenyl)-2,5-dimethylpyrazine 1-oxide but substitutingPreparation of 3-(2,4-dichlorophenyl)-2,5-diethylpyrazine and makingnon-critical variations, the title compound was obtained (quantitative).It was used without preparation. ¹H NMR (CDCl₃) δ1.12, 1.34, 2.55, 2.81,2.89, 7.28, 7.40, 7.55, 8.11.

[0560] Preparation 25

[0561] Preparation of 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine

[0562] Following the procedure of2-bromo-5-(2,4-dichlorophenyl)-3,6-dimethylpyrazine but substituting3-(2,4-dichlorophenyl)-2,5-diethylpyrazine 1-oxide and makingnon-critical variations provided the title compound as an oil: ¹H NMR(CDCl₃) δ1.19 7.5, 1.33, 2.63, 3.02, 7.28, 7.39, 7.54; MS (ESI+) forC₁₄H₁₃Br₁Cl₂N₂ m/z 361.1 (M+H)⁺.

Example 33

[0563] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(3-ethyl-6-methylpyridin-2-yl)pyrazin-2-amine

[0564] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and3-ethyl-6-methylpyridin-2-amine, and making non-critical variationsprovided the title compound as a oil: ¹H NMR (DMSO-d₆) δ0.95, 1.15,2.33, 2.31, 2.51, 2.70, 6.95, 7.51, 7.75, 8.57; HRMS (ESI+) calcd forC₂₂H₂₄Cl₂N₄ (M+H)⁺ 415.1456, found 415.1442.

Example 34

[0565] Preparation of5-(2,4-dichlorophenyl)-N-(4,6-dimethylpyridin-2-yl)-3,6-diethylpyrazin-2-amine

[0566] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and4,6-dimethylpyridin-2-amine, and making non-critical variations providedthe title compound as a oil: ¹H NMR (CDCl₃) δ1.31, 1.38, 2.37, 2.46,2.62, 2.90, 6.68, 7.31, 7.37, 7.52, 8.28; HRMS (ESI+) Calcd forC₂₁H₂₂Cl₂N₄ (M+H)⁺ 401.1299, found 401.1317.

[0567] Preparation 26

[0568] Preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine

[0569] To a solution of 6,7-dihydro-1-benzofuran-4(5H)-one (2.0 g) inmethanol (50 ml) was added 3 Å sieves (15 g), ammonium acetate (11.3 g)and sodium cyanoborohydride (1.22 g). After 48 h of stirring, thereaction mixture was filtered through celite, concentrated, dissolved in1 N HCl (100 ml) and washed with ethyl ether (3×100 ml). The Aqueouslayer was basified to pH 10 (NaOH), extracted methylene chloride (3×100ml), dried MgSO₄, filtered and concentrated to yield (760 mg, 38%) ofthe title compound as an oil: ¹H NMR (400 MHz, CDCl₃) δ7.27, 6.39, 3.87,2.61, 2.00, 1.81, 1.48; ¹³C NMR (100 MHz, CDCl₃) δ151.47, 141.11,122.31, 109.29, 45.93, 34.81, 23.38, 20.63.

[0570] Preparation 27

[0571] Preparation of3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine

[0572] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 4,5,6,7-tetrahydro-1-benzofuran-4-amine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ7.66, 7.29, 6.32, 5.25, 4.40, 2.69, 2.57, 2.07, 1.92,1.36; (MS/CI) calcd for C₁₆H₂₁N₃O+H 272.1, found 272.1.

[0573] Preparation 28

[0574] Preparation of5-bromo-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine

[0575] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (400 MHz, CDCl₃) δ7.29, 6.03, 5.18, 4.49, 2.81, 2.65, 2.55, 2.03,1.89, 1.23; (FAB) calcd for C₁₆H₂₀BrN₃O+H 351.0, found 351.0.

Example 35

[0576] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine

[0577] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (400 MHz, CDCl₃) δ7.50, 7.34, 5.30, 4.53, 2.68, 2.62, 2.51, 2.09,1.94 1.26, 1.20; HRMS (EI) calcd for C₂₂H₂₃Cl₂N₃O 415.1218, found415.1217.

[0578] Preparation 29

[0579] Preparation of 5-methyl-6,7-dihydro-1-benzofuran-4(5H)-one

[0580] Following the procedure for the preparation of5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting6,7-dihydro-1-benzofuran-4(5H)-one and making non-critical variationsprovided the title compound as a oil: ¹H NMR (CDCl₃) δ1.24, 1.95, 2.25,2.55, 2.93, 6.68, 7.33; MS (EI) m/z (rel. intensity) 150 (M+, 54), 150(54), 121 (10), 109 (8), 108 (99), 86 (26), 84 (39), 80 (56), 52 (19),51 (26), 50 (7). HRMS (FAB) calcd for C₉H₁₀O₂+H 151.0759, found151.0760. Anal. Calcd for C₉H₁₀O₂: C, 71.98; H, 6.71. Found: C, 71.55;H, 6.74; N, 0.19.

[0581] Preparation 30

[0582] Preparation of 5-methyl-4,5,6,7-tetrahydro-1-benzofuran-4-amine

[0583] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting5-methyl-6,7-dihydro-1-benzofuran-4(5H)-one and making non-criticalvariations provided the title compound as a oil: MS (EI) m/z (rel.intensity) 151 (M+, 64), 151 (64), 134 (86), 110 (83), 109 (99), 108(55), 88 (56), 86 (87), 84 (92), 80 (76), 51 (67). HRMS (FAB) calcd forC₉H₁₃NO+H 152.1075, found 152.1066.

Example 36

[0584] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine

[0585] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ1.13, 1.19, 1.26, 1.78, 2.04, 2.50, 2.65, 4.50, 5.02, 6.,7.31, 7.50; HRMS (ESI+) calcd for C₂₃H₂₅Cl₂N₃O₁ (M+H)⁺ 480.1453, found430.1436.

[0586] Preparation 31

[0587] Preparation of 5-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one

[0588] Following the procedure for the preparation of5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting6,7-dihydro-1-benzofuran-4(5H)-one and ethyl iodide and makingnon-critical variations provided the title compound as a oil: ¹H NMR(CDCl₃) δ1.00, 1.54, 1.95, 2.29, 2.91, 6.67, 7.3; MS (EI) m/z (rel.intensity) 164 (M+, 36), 164 (36), 136 (90), 135 (24), 108 (76), 88(13), 86 (69), 84 (99), 80 (58), 52 (21), 51 (57). HRMS (FAB) calcd forC₁₀H₁₂O₂+H 165.0916, found 165.0919. Anal. Calcd for C₁₀H₁₂O₂: C, 73.15;H, 7.37. Found: C, 72.81; H, 7.60.

[0589] Preparation 32

[0590] Preparation of (4E) and(4Z)-5-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one oxime

[0591] Following the procedure for the preparation of(4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting5-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one and making non-criticalvariations provided the title compound as a oil: MS (EI) m/z (rel.intensity) 179 (M+, 21), 162 (50), 151 (43), 135 (99), 134 (99), 107(86), 106 (83), 84 (34), 79 (35), 52 (47), 51(48). HRMS (FAB) calcd forC₁₀H₁₃NO₂+H 180.1024, found 180.1015.

[0592] Preparation 33

[0593] Preparation of cis5-ethyl-4,5,6,7-tetrahydro-1-benzofuran-4-amine

[0594] Following the procedure for the preparation ofcis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine but substituting(4E) and (4Z)-5-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one oxime andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ1.02, 1.30-1.73, 2.50-2.67, 3.84, 6.38, 7.27; HRMS (FAB)calcd for C₁₀H₁₅NO+H 166.1232, found 166.1231. Anal. Calcd for C₁₀H₁₅NO:C, 72.69; H, 9.15; N, 8.48. Found: C, 72.33; H, 9.14; N, 8.08.

[0595] Preparation 34

[0596] Preparation of trans5-ethyl-4,5,6,7-tetrahydro-1-benzofuran-4-amine

[0597] Following the procedure for the preparation ofcis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine but substituting(4E) and (4Z)-5-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one oxime andmaking non-critical variations provided the title compound as a oil: ¹HNMR(CDCl₃) δ1.02, 1.30-1.73, 2.50-2.67, 4.46, 6.10, 7.24; HRMS (FAB)calcd for C₁₀H₁₅NO+H 166.1232, found 166.1231. Anal. Calcd for C₁₀H₁₅NO:C, 72.69; H, 9.15; N, 8.48. Found: C, 72.33; H, 9.14; N, 8.08

Example 37

[0598] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(cis)-5-ethyl-4,5,6,7-tetrahydro-1-benzofuran-4-yl]pyrazin-2-amine

[0599] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting cis 5-ethyl-4,5,6,7-tetrahydro-1-benzofuran-4-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ0.89, 1.11, 1.16, 1.53-1.65, 1.86, 2.42-2.49, 2.53,2.65-2.74, 3.66, 3.77, 4.21, 5.48, 6.27, 7.01, 7.10-7.31, 7.40; MS (EI)m/z (rel. intensity) 443 (M+, 29), 443 (29), 296 (22), 295 (23), 207(39), 149 (99), 148 (57), 119 (39), 107 (23), 91 (45), 55 (22). HRMS(FAB) calcd for C₂₄H₂₇Cl₂N₃O+H 444.1609, found 444.1610.

Example 38

[0600] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(cis)-5-ethyl-4,5,6,7-tetrahydro-1-benzofuran-4-yl]pyrazin-2-amine

[0601] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting trans-5-ethyl-4,5,6,7-tetrahydro-1-benzofuran-4-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ1.05, 1.17, 1.29, 1.80, 1.90, 2.04, 2.49, 2.63, 3.49, 3.83,4.50, 5.11, 6.32, 7.30-7.38, 7.50; HRMS (FAB) calcd for C₂₄H₂₇Cl₂N₃O+H444.1609, found 444.1600.

[0602] Preparation 35

[0603] Preparation of 3,4-dihydro-2H-thiochromen-4-ylamine

[0604] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting2,3-dihydro-4H-thiochromen-4-one and making non-critical variationsprovided the title compound as a oil: ¹H NMR (300 MHz, CDCl₃) δ7.30,7.07, 4.07, 3.28, 2.96, 2.16, 1.61; (MS/CI) calcd for C₉H₁₁NS+H 166.3,found 166.3.

[0605] Preparation 36

[0606] Preparation ofN-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amine

[0607] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 3,4-dihydro-2H-thiochromen-4-ylamine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ7.71, 7.30, 7.15, 7.05, 5.44, 4.51, 3.17, 2.98, 2.68,2.64, 2.56, 2.14, 1.31; HRMS (FAB) calcd for C₁₇H₂₁N₃S+H 300.1534, found300.1532.

[0608] Preparation 37

[0609] Preparation of5-bromo-N-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amine

[0610] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substitutingN-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (400 MHz, CDCl₃) δ7.28, 7.19, 7.04, 5.38, 4.50, 3.53, 2.99, 2.84,2.64, 2.55, 2.13, 1.31, 1.24; ¹³C NMR (100 MHz, CDCl₃) δ152.50, 149.99,141.71, 134.14, 134.03, 131.10, 128.59, 127.30, 125.65, 124.88, 48.74,29.40, 27.58, 25.83, 23.05, 12.52, 11.26; HRMS (EI) calcd forC₁₇H₂₀BrN₃S 377.0562, found 377.0565.

Example 39

[0611] Preparation of5-(2,4-dichlorophenyl)-N-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amine

[0612] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-N-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ7.51, 7.36, 7.32, 7.29, 7.20, 7.07, 5.49, 4.64,3.23, 3.02, 2.72, 2.64, 2.53, 2.20, 1.27, 1.22; ¹³C NMR (100 MHz, CDCl₃)δ151.42, 150.26, 140.63, 137.74, 137.67, 135.29, 134.57, 134.22, 132.88,131.23, 129.81, 129.11, 128.53, 127.52, 127.28, 124.87, 48.48, 27.58,26.34, 23.18, 23.11, 13.30, 11.64; HRMS (FAB) calcd for C₂₃H₂₃Cl₂N₃S+H444.1068, found 444.1055.

[0613] Preparation 38

[0614] Preparation of3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0615] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 1,2,3,4-tetrahydronaphthalen-1-amine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ7.81, 7.38, 7.19, 5.49, 4.56, 2.87, 2.69, 2.57, 2.12,1.98, 1.91, 1.32; 13C NMR (100 MHz, CDCl3) δ153.69, 151.42, 140.81,138.70, 138.29, 129.85, 129.56, 129.18, 127.49, 126.58, 48.71, 30.07,29.94, 28.56, 26.07, 20.42, 13.96, 11.16; HRMS (FAB) calcd forC₁₈H₂₃N₃+H 282.1970, found 282.1975.

[0616] Preparation 39

[0617] Preparation of5-bromo-3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0618] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (400 MHz, CDCl₃) δ7.34, 7.21, 5.40, 4.54, 2.55, 2.09, 1.95, 1.28;¹³C NMR (100 MHz, CDCl₃) δ152.49, 150.66, 141.49, 138.29, 138.21,129.63, 129.27, 127.64, 126.65, 124.90, 60.81, 49.31, 29.89, 28.87,29.39, 21.46, 20.32, 14.61, 11.26. (MS/CI) calcd for C₁₈H₂₂BrN₃+H 360.3,found 360.3.

Example 40

[0619] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0620] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ7.40, 7.32, 7.20, 7.08, 5.41, 4.57, 2.80, 2.53,2.41, 2.06, 1.96, 1.90, 1.18; ¹³C NMR (100 MHz, CDCl₃) δ151.50, 150.93,140.37, 138.53, 138.37, 137.87, 137.123, 135.36, 134.43, 132.95, 129.78,129.62, 129.44, 127.57, 127.51, 125.63, 60.82, 49.01, 29.96, 27.62,26.93, 14.61, 13.32, 11.67; HRMS (FAB) calcd for C₁₈H₂₂BrN₃+H 360.1076,found 360.1065.

Example 41

[0621] Preparation of2-(2,4-dichlorophenyl)-3,6-diethyl-5-(1,2,3,4-tetrahydronaphthalen-1-yloxy)pyrazine

[0622] A solution of 1,2,3,4-tetrahydronaphthalen-1-ol (248 mg) in DMSO(3 ml) was added to NaH (100 mg) suspended in DMSO (4 ml). The reactionmixture was stirred at r.t. for 1 hour and heated at 75° C. for 1 hour.2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine in DMSO (3 ml) wasadded. After 24 h, the rxn mixture was diluted with 30 ml of H₂O,extracted with CH₂Cl₂, washed with NaHCO₃, brine, dried (MgSO₄),filtered and concentrated. Flash chromatography (1:50 EtOAC:Heptane)gave the title compound: ¹H NMR (CDCl₃) δ1.23, 1.95, 2.13, 2.20, 2.58,2.83, 2.96, 6.46, 7.36; HRMS (ESI+) calcd for C₂₄H₂₄Cl₂N₂O₁ (M+H)⁺427.1344, found 427.1359.

[0623] Preparation 40

[0624] Preparation of 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine

[0625] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting7-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-criticalvariations provided the title compound as a oil: ¹H NMR (400 MHz, CDCl₃)δ6.99, 6.75, 3.95, 3.82, 2.74, 2.05, 1.96, 1.71, 1.67, 1.56; ¹³C NMR(100 MHz, CDCl₃) δ158.28, 142.62, 130.30, 129.19, 113.44, 112.88, 55.73,50.12, 34.17, 29.12, 20.26.

[0626] Preparation 41

[0627] Preparation of3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0628] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 7-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ7.67, 7.08, 6.92, 6.81, 5.42, 4.54, 3.75, 2.84-2.77,2.68, 2.56, 2.10, 1.88, 1.36-1.27; (MS/CI) calcd for C₁₉H₂₅N₃O+H 312.4,found 312.1.

[0629] Preparation 42

[0630] Preparation of5-bromo-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0631] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ7.08, 6.88, 6.81, 5.36, 4.52, 3.76, 2.79, 2.56,2.08, 1.91, 1.31; (FAB) calcd for C₁₉H_(24Br)N₃O+H 390.0, found 390.0.

Example 42

[0632] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0633] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ7.51, 7.34, 7.10, 6.99, 6.83, 5.47, 4.68, 3.78,2.85, 2.65, 2.53, 2.15, 2.01, 1.27, 1.21; ¹³C NMR (100 MHz, CDCl₃)δ173.14, 157.25, 150.37, 149.81, 139.28, 138.42, 136.72, 136.05, 134.21,133.33, 131.82, 129.41, 129.26, 128.65, 126.39, 112.41, 54.61, 48.17,28.92, 28.00, 26.49, 25.27, 19.52, 12.19, 10.54; HRMS (FAB) calcd forC₂₅H₂₇Cl₂N₃O+H 456.1609, found 456.1601.

Example 43

[0634] Preparation of5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0635] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amineand 2-chloro-4-methoxyphenylboronic acid, and making non-criticalvariations provided the title compound as a oil: ¹H NMR (400 MHz, CDCl₃)δ7.29, 7.11, 7.04, 6.99, 6.91, 6.84, 5.47, 4.64, 3.86, 3.78, 2.83, 2.68,2.55, 2.15, 1.91, 1.74, 1.27, 1.21; ¹³C NMR (100 MHz, CDCl₃) δ160.08,158.37, 151.72, 150.71, 140.19, 139.72, 138.22, 136.12, 135.06, 132.59,131.63, 130.50, 130.39, 115.13, 114.20, 113.41, 55.99, 55.74, 49.29,30.08, 29.16, 27.66, 26.50, 20.66, 13.35, 11.82; HRMS (FAB) calcd forC₂₆H₃₀ClN₃O₂+H 452.2104, found 452.2097.

[0636] Preparation 43

[0637] Preparation of 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine

[0638] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting5-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-criticalvariations provided the title compound as a oil: ¹H NMR (400 MHz, CDCl₃)δ7.19, 7.05, 6.75, 4.00, 3.84, 2.76, 2.61, 1.97, 1.70; ¹³C NMR (100 MHz,CDCl₃) δ157.44, 142.83, 126.67, 126.02, 120.53, 108.09, 55.72, 49.75,33.21, 23.57, 19.11; HRMS (FAB) calcd for C₁₁H₁₅NO+H 178.1232, found178.1233.

[0639] Preparation 44

[0640] Preparation of3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0641] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 5-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ7.66, 7.19, 7.00, 6.78, 5.47, 4.54, 3.87, 2.83, 2.68,2.54, 2.06, 2.02, 1.97, 1.31; ¹³C NMR (100 MHz, CDCl₃) δ157.50, 153.66,161.36, 140.81, 139.90, 129.80, 127.37, 126.82, 121.33, 108.49, 55.75,48.72, 29.44, 28.55, 26.08, 23.59, 19.62, 13.93, 11.14; HRMS (FAB) calcdfor C₁₉H₂₅N₃O+H 312.2076, found 312.2066.

[0642] Preparation 45

[0643] Preparation of5-bromo-3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0644] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amineand making non-critical variations provided the title compound as a oil:1H NMR (400 MHz, CDCl3) δ) 7.18, 6.97, 6.79, 5.37, 4.53, 2.87-2.76,2.70-2.64, 2.54, 2.01-1.86, 1.35-1.24; HRMS (FAB) calcd forC₁₉H₂₄BrN₃O+H 390.1181, found 390.1186.

Example 44

[0645] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0646] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ) 7.51, 7.33, 7.23, 7.07, 6.81, 5.50, 4.68,3.89, 2.87-2.80, 2.72-2.61, 2.12-2.01, 1.91, 1.30-1.19; HRMS (FAB) calcdfor C₂₅H₂₇Cl₂N₃O+H 456.1609, found 456.1627.

[0647] Preparation 46

[0648] Preparation of 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine

[0649] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting6-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-criticalvariations provided the title compound as a oil: ¹H NMR (400 MHz, CDCl₃)δ7.34, 6.78, 6.63, 3.97, 3.79, 2.74, 1.77, 1.89; ¹³C NMR (100 MHz,CDCl₃) δ158.47, 138.45, 133.91, 129.64, 113.71, 112.67, 55.61, 49.23,34.25, 30.31, 24.6, 23.23, 19.87.

[0650] Preparation 47

[0651] Preparation of3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0652] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and makingnon-critical variations provided the title compound as a oil: HRMS (FAB)calcd for C₁₉H₂₅N₃O+H 312.2076, found 312.2075; Anal. Calcd forC₁₉H₂₅N₃O: C, 73.28; H, 8.09; N, 13.49. Found C, 73.38; H, 8.11; N,13.32.

[0653] Preparation 48

[0654] Preparation of5-bromo-3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0655] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ) 7.26, 6.78, 6.69, 5.33, 4.49, 3.82,2.89-2.78, 2.55, 2.05-1.84, 1.33-1.26; HRMS (FAB) calcd forC₁₉H₂₄BrN₃O+H 390.1181, found 390.1180.

Example 45

[0656] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0657] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (400 MHz, CDCl₃) δ) 7.51, 7.31, 6.81, 6.71, 5.44, 4.63,3.83, 2.93-2.76, 2.66-2.51, 2.10, 1.91, 1.32-1.14; HRMS (FAB) calcd forC₂₅H₂₇Cl₂N₃O+H 456.1609, found 456.1624; Anal. Calcd for C₂₅H₂₇Cl₂N₃O:C, 65.79; H, 5.96; N, 9.21. Found: C, 65.58; H, 5.96; N, 8.99.

[0658] Preparation 49

[0659] Preparation of Racemic Mixture of(trans)-1-amino-1,2,3,4-tetrahydronaphthalen-2-ol

[0660] To a mixture of 1,2-dihydronaphthalene (5.12 g) andtrifluoroacetone (1.34 g) in acetonitrile (60 ml) and aqueous potassiumcarbonate (1.5M in 0.4 mM EDTA, 60 ml) was added H₂O₂ (30%, 18.2 ml) at0° C. Upon stirring at 0° C. for 4 hours, the rxn mixture was extractedwith Et₂O, washed with aqueous Na₂S₂O₃ (1M) and brine, dried (MgSO₄),filtered and concentrated. The epoxide was used without purification. Amixture of 1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene and ammoniumhydroxide was stirred at 40° C. for 3 days. The excess solvent wasremoved in vacuo. Flash chromatography (Silica gel, 1:20 MeOH: CH₂Cl₂,0.5% NH₄OH) gave the title compound. HRMS (FAB) calcd for C₁₀H₁₃NO+H164.1075, found 164.1075.

[0661] Preparation 50

[0662] Preparation of(trans)-1-[(3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol

[0663] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting (trans)-1-amino-1,2,3,4-tetrahydronaphthalen-2-ol andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ1.27-1.34, 2.01, 2.24, 2.64, 2.84, 2.93, 4.03, 4.76, 5.06,5.17, 7.19-7.21, 7.25-7.27, 7.34-7.37, 7.66;

[0664] Preparation 51

[0665] Preparation of Racemic Mixture oftrans-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol

[0666] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting(trans)-1-[(3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-oland making non-critical variations provided the title compound as a oil:¹H NMR (CDCl₃) δ1.30 (m, 6 H), 1.95 (m, 1 H), 2.25 (m, 1 H), 2.64 (dd,J=7.5, 15.1 Hz, 2 H), 2.84 (dd, J=7.6, 15.2 Hz, 2 H), 2.94 (m, 2 H),4.03 (m, 1 H), 4.74 (d, J=6.7 Hz, 1 H), 5.08 (s, 1 H), 5.16 (dd, J=6.7,7.2 Hz, 1 H), 7.2 (m, 1 H), 7.28 (m, 2 H), 7.35 (m, 1 H); MS (EI) m/z(rel. intensity) 375 (M+, 9), 359 (68), 357 (67), 230 (45), 146 (35),129 (69), 128 (56), 118 (55), 117 (99), 115 (68), 91 (45). HRMS (FAB)calcd for C₁₈H₂₂BrN₃O+H 376.1025, found 376.1029. Anal. Calcd forC₁₈H₂₂BrN₃O: C, 57.45; H, 5.89; N, 11.17; Br, 21.23. Found: C, 57.61; H,5.88; N, 10.70.

[0667] Preparation 52

[0668] Preparation of Racemic Mixtures oftrans-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

[0669] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substitutingtrans-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (CDCl₃) δ1.10, 1.23, 1.85, 2.20, 2.44, 2.62, 2.87,3.97, 4.83, 5.14, 5.97, 7.12-7.27, 7.43; HRMS (FAB) calcd forC₂₄H₂₅Cl₂N₃O+H 442.1453, found 442.1448.

Example 46

[0670] Preparation of Racemic Mixture of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2R) and(1S,2S)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine

[0671] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting (1R,2R) and(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-oland methyl iodide, and making non-critical variations provided the titlecompound as a oil: ¹H NMR (CDCl₃) δ1.28, 2.04, 2.12, 2.53, 2.60, 2.78,3.05, 3.59, 3.98, 4.55, 5.39, 7.19-7.43, 7.51; HRMS (FAB) calcd forC₂₅H₂₇Cl₂N₃O+H 456.1609, found 456.1598. Anal. Calcd for C₂₅H₂₇Cl₂N₃O:C, 65.79; H, 5.96; N, 9.21; Cl, 15.54. Found: C, 65.80; H, 6.08; N, 9.09

Example 47

[0672] Preparation of Racemic Mixture of5-(2,4-dichlorophenyl)-N-[(1R,2R)and(1S,2S)-2-ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-3,6-diethylpyrazin-2-amine

[0673] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting (1R,2R) and(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-oland making non-critical variations provided the title compound as a oil:¹H NMR (CDCl₃) δ0.81, 1.10-1.23, 1.91, 1.99, 2.43, 2.51, 2.67, 2.96,3.70, 3.95, 4.46, 5.25, 7.10-7.28, 7.42; HRMS (FAB) calcd forC₂₈H₃₃Cl₂N₃O+H 498.2079, found 498.2079

[0674] Preparation 53

[0675] Preparation of Racemic Mixturetrans-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-yl4-nitrobenzoate

[0676] Following the procedure for the preparation of benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-[(4-nitrobenzoyl)oxy]pyrrolidine-1-carboxylatebut substitutingtrans-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-yl4-nitrobenzoate and making non-critical variations provided the titlecompound as a oil: ¹H NMR (CDCl₃) δ1.15-1.23, 2.23, 2.40, 2.54, 2.68,3.01, 3.10, 4.62, 5.77, 5.94, 7.23-7.30, 7.40, 7.95, 8.22.

[0677] Preparation 54

[0678] Preparation of Racemic Mixture ofcis-(5-bromo-3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol

[0679] Following the procedure for the preparation of benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylatebut substitutingtrans-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-yl4-nitrobenzoate and making non-critical variations provided the titlecompound as a oil: ¹H NMR (CDCl₃) δ1.24-1.32, 2.07, 2.62, 2.84, 2.87,3.02, 4.29, 4.39, 4.63, 5.36, 7.18-7.29; ¹³C NMR (CDCl₃) δ11.22, 12.56,25.94, 26.94, 27.39, 29.33, 32.29, 55.13, 70.92, 125.84, 127.09, 128.44,129.41, 130.12, 135.89, 137.71, 142.35, 151.62, 151.91.

Example 48

[0680] Preparation of Racemic Mixture ofcis-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

[0681] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substitutingcis-(5-bromo-3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (CDCl₃) δ1.18-1.31, 2.09, 2.54, 2.64, 2.95, 2.99, 4.33,4.69, 5.43, 7.22-7.35, 7.51; HRMS (FAB) calcd for C₂₄H₂₅Cl₂N₃O+H442.1453, found 442.1454.

Example 49

[0682] Preparation of Racemic Mixture of(cis)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine

[0683] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substitutingcis-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-oland methyl iodide, and making non-critical variations provided the titlecompound as a oil: ¹H NMR (CDCl₃) δ1.12, 1.30, 1.99, 2.35, 2.47, 2.74,3.06, 3.46, 3.89, 5.41, 5.80, 7.18, 7.35, 7.51; HRMS (FAB)calcd forC₂₅H₂₇Cl₂N₃O+H 456.1609, found 456.1617.

Example 50

[0684] Preparation of Racemic Mixture of5-(2,4-dichlorophenyl)-N-[(cis)-2-ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-3,6-diethylpyrazin-2-amine

[0685] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(cis)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ1.14, 1.20, 1.29, 1.95, 2.31, 2.45, 2.73, 2.82, 3.12, 3.48,3.74, 3.99, 5.42, 5.75, 7.12-7.21, 7.36, 7.51; HRMS (FAB) calcd forC₂₅H₂₇Cl₂N₃O+H 456.1609, found 456.1617.

[0686] Preparation 55

[0687] Preparation of 4,5,6,7-tetrahydro-1-benzothiophen-4-amine

[0688] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting6,7-dihydro-1-benzothiophen-4(5H)-one and making non-critical variationsprovided the title compound as a oil: ¹H NMR (400 MHz, CDCl₃) δ7.09,7.02, 3.95, 2.79, 2.03, 1.85, 1.62; ¹³C NMR (100 MHz, CDCl₃) δ140.51,137.18, 126.77, 122.66, 47.96, 34.24, 25.48, 21.48;

[0689] Preparation 56

[0690] Preparation of3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine

[0691] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 4,5,6,7-tetrahydro-1-benzothiophen-4-amine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ7.67 (s, 1 H), 7.10 (d, J=5.2 Hz, 1 H), 6.93 (d, J=5.2Hz, 1 H), 5.40 (m, 1 H), 4.50 (bs, 1 H), 2.83 (m, 2 H), 2.66 (q, J=7.5Hz, 2 H), 2.56 (q, J=7.5 Hz, 2 H), 2.10 (m, 1H), 1.96 (m, 3 H), 1.29 (m,6 H); (MS/CI) calcd for C₁₆H₂₁N₃S+H 287.4, found 287.9.

[0692] Preparation 57

[0693] Preparation of5-bromo-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine

[0694] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (300 MHz, CDCl₃) δ7.10, 6.91, 5.32, 4.47, 2.83, 2.53, 2.10, 1.93,1.27; (MS/CI) calcd for C₁₆H₂₀BrN₃S+H 369.9, found 369.9.

Example 51

[0695] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine

[0696] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ7.51, 7.39, 7.12, 6.99, 5.45, 4.64, 2.90, 2.65,2.51, 2.20, 1.99, 1.27, 1.20; ¹³C NMR (100 MHz, CDCl₃) δ151.51, 150.78,140.47, 139.15, 137.82, 137.21, 135.35, 134.47, 132.93, 128.78, 127.51,127.37, 123.01, 117.71, 46.74, 29.97, 27.62, 26.36, 25.53, 21.37,12.32,11.63; HRMS (FAB) calcd for C₂₂H₂₃Cl₂N₃S+H 432.1068, found 432.1073.

[0697] Preparation 58

[0698] Preparation of 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one

[0699] To a solution of 6,7-dihydro-1-benzothiophen-4(5H)-one (1.63 g)in tetrahydrofuran (90 ml) at −78° C. under N₂ was added lithiumdiisopropyl amide (5.89 ml, 2 M). After 30 min, iodomethane (0.732 ml)was added and the reaction was allowed to warm to ambient temperature.After 2 h, the reaction mixture was poured into saturated sodiumbicarbonate (100 ml), extracted methylene chloride (3×100 ml), driedMgSO₄, filtered and concentrated. MPLC was run on a biotage 40M columnwith 4-6% ethyl acetate/heptane to provide the title compound as an oil(560 mg, 32%): 1H NMR (300 MHz, CDCl3) δ) 7.41, 7.08, 3.15-2.99,2.61-2.53, 2.33-2.25, 2.06-1.92, 1.28; HRMS (FAB) calcd for C₉H₁₀OS+H167.0531, found 167.0527.

[0700] Preparation 59

[0701] Preparation of 5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-ylamine

[0702] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one and making non-criticalvariations provided the title compound as a oil: ¹H NMR (400 MHz, CDCl₃)δ) 7.12-6.99, 4.13, 3.89, 3.51, 2.86-2.74, 2.13-1.98, 1.75, 1.65, 1.15,1.07.

[0703] Preparation 60

[0704] Preparation of3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine

[0705] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-ylamine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (400 MHz, CDCl₃) δ) 7.66, 7.07, 6..91, 6.83, 5.62, 5.15, 4.46, 4.35,3.09, 2.65-2.55, 2.28, 2.06-1.97, 1.80, 1.29, 1.11, 1.01; (MS/CI) calcdfor C₁₇H₂₃N₃S+H 301.6, found 301.9.

[0706] Preparation 61

[0707] Preparation of5-bromo-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine

[0708] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ) 7.08, 6.87, 6.80, 5.55, 5.08, 4.45, 4.40,2.91-2.78, 2.58, 2.22, 2.05-1.98, 1.79, 1.28, 1.10, 1.00.

Example 52

[0709] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Cis-5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0710] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (400 MHz, CDCl₃) δ) 7.51, 7.33, 7.11; 6.96, 5.66, 4.52,2.95-2.62, 2.55, 2.38, 2.05, 1.97, 1.79, 1.26, 1.20, 1.07; HRMS (FAB)calcd for C₂₃H₂₅Cl₂N₃S+H 446.1224, found 446.1224.

Example 53

[0711] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Trans-5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0712] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (400 MHz, CDCl₃) δ) 7.50, 7.35-7.30, 7.10, 6.90, 5.18,4.60, 2.85, 2.66, 2.49, 2.05, 1.82, 1.29-1.12; HRMS (FAB) calcd forC₂₃H₂₅Cl₂N₃S+H 446.1224, found 446.1230. Anal. Calcd for C₂₃H₂₅Cl₂N₃S:C, 61.88; H, 5.64; N, 9.41; Cl, 15.88; S, 7.18. Found: C, 62.04; H,5.77; N, 9.04.

[0713] Preparation 62

[0714] Preparation of 5-ethyl-6,7-dihydro-1-benzothiophen-4(5H)-one

[0715] Following the procedure for the preparation of5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substitutingiodoethane and making non-critical variations provided the titlecompound as a oil: ¹H NMR (300 MHz, CDCl₃) δ) 7.40, 7.07, 3.18-2.96,2.43-2.27, 2.09-1.94, 1.59, 1.02. HRMS (FAB) calcd for C₁₀H₁₂OS+H181.0687, found 181.0684. Anal. Calcd for C₁₀H₁₂OS: C, 66.63; H, 6.71.Found: C, 66.50; H, 6.75.

[0716] Preparation 63

[0717] Preparation of 5-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine

[0718] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting5-ethyl-6,7-dihydro-1-benzothiophen-4(5H)-one and making non-criticalvariations provided the title compound as a oil: ¹H NMR (400 MHz, CDCl₃)δ) 7.10, 7.05, 6.99, 3.98, 3.65, 2.87-2.73, 2.06-1.90, 1.74-1.19,1.05-0.97. (MS/CI) calcd for C₁₀H₁₅NS+H 182.3, found 181.9.

Example 54

[0719] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Cis-5-ethyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0720] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting cis-5-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ; 7.50, 7.32, 7.08, 6.98, 5.77, 4.42, 2.99, 2.95,2.62, 2.50, 1.98, 1.73, 1.39-1.18, 1.00; HRMS (FAB) calcd forC₂₄H₂₇Cl₂N₃S+H 460.1381, found 460.1376.

Example 55

[0721] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Trans-5-ethyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0722] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting trans-5-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amineand 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ) 7.50, 7.35-7.28, 7.11, 6.91, 5.27, 4.58, 2.85, 2.64,2.49, 2.08, 1.93, 1.84, 1.66, 1.41, 1.26, 1.18, 1.06; HRMS (FAB) calcdfor C₂₄H₂₇Cl₂N₃S+H 460.1381, found 460.1398. Anal. Calcd forC₂₄H₂₇Cl₂N₃S: C, 62.60; H, 5.91; N, 9.13. Found: C, 62.36; H, 5.94; N,8.91.

[0723] Preparation 64

[0724] Preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime

[0725] To a solution of 2,3-dihydro-4H-chromen-4-one (3.00 g) in ethanol(15 ml)/water (3 ml) was added sodium acetate (6.64 g) and hydroxylamine hydrochloride (5.52 g). The reaction mixture was heated at 70° C.for 1 h, poured into saturated sodium bicarbonate (50 ml), extractedmethylene chloride (3×50 ml), dried MgSO₄, filtered and concentrated toprovide the title compound as a solid (3.22 g, 99%): ¹H NMR (300 MHz,CDCl₃) δ) 7.86, 7.28, 7.00-6.91, 4.27, 3.02; HRMS (FAB) calcd forC₉H₉NO₂+H 164.0712, found 164.0703. Anal. Calcd for C₉H₉NO₂: C, 66.25;H, 5.56; N, 8.58. Found: C, 66.21; H, 5.58; N, 8.57.

[0726] Preparation 65

[0727] Preparation of 3,4-dihydro-2H-chromen-4-ylamine

[0728] To a solution of (4E)-2,3-dihydro-4H-chromen-4-one oxime (3.20 g)in tetrahydrofuran (50 ml) under N₂ atmosphere was added lithiumaluminum hydride (1M THF, 50 ml). The reaction mixture stirred atambient temperature for 16 h and was quenched with 10 ml of water, 10 mlof 2 N NaOH and 20 ml of water. The reaction mixture was filteredthrough celite, acidified with 1 N HCl (50 ml), washed with ethyl ether(2×50 ml), basified with 2 N NaOH, extracted methylene chloride (3×100ml), dried MgSO₄, filtered and concentrated. MPLC was run on a biotage40S column with 2-4% methanol/methylene chloride with 0.5% ammoniumhydroxide to provide the title compound as an oil (728 mg, 25%): ¹H NMR(300 MHz, CDCl₃) δ) 7.34, 7.17, 6.92, 6.85, 4.31-4.24, 4.09, 2.18,1.91-1.86; HRMS (FAB) calcd for C₉H₁₁NO+H 150.0919, found 150.0910.

[0729] Preparation 66

[0730] Preparation ofN-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine

[0731] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 3,4-dihydro-2H-chromen-4-ylamine and making non-criticalvariations provided the title compound as a oil: ¹H NMR (300 MHz, CDCl₃)δ) 7.71, 7.31-7.21, 6.95, 6.91, 5.34, 4.54, 4.32-4.24, 2.71, 2.56, 2.25,1.36-1.26; HRMS (FAB) calcd for C₁₇H₂₁N₃O+H 284.1763, found 284.1768.

[0732] Preparation 67

[0733] Preparation of5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine

[0734] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substitutingN-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(300 MHz, CDCl₃) δ) 7.28-7.21, 6.96-6.89, 5.26, 4.54, 4.29-4.22, 2.84,2.57, 2.22, 1.32-1.24; HRMS (FAB) calcd for C₁₇H₂₀BrN₃O+H 362.0868,found 362.0861. Anal. Calcd for C₁₇H₂₀BrN₃O: C, 56.36; H, 5.56; N,11.60. Found: C, 56.10; H, 5.56; N, 11.35.

Example 56

[0735] Preparation of5-(2,4-dichlorophenyl)-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine

[0736] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (300 MHz, CDCl₃) δ); 7.51, 7.36-7.23, 6.98-6.90, 5.37,4.69, 4.32, 2.66, 2.51, 2.31, 1.29-1.17; HRMS (EI) calcd forC₂₃H₂₃Cl₂N₃O 427.1218, found 427.1224.

Example 57

[0737] Preparation of5-(2-chloro-4-methylphenyl)-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine

[0738] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine,ethylene glycol dimethyl ether, 2-chloro-4-methyl phenyl boronic acidand tetrakis(triphenylphosphine) palladium and making non-criticalvariations provided the title compound as a oil: ¹H NMR (300 MHz, CDCl₃)δ) 7.37-7.13, 6.99-6.90, 5.37, 4.64, 4.31, 2.69, 2.54, 2.40, 2.30,1.29-1.17; HRMS (FAB) calcd for C₂₄H₂₆ClN₃O+H 408.1842, found 408.1848.Anal. Calcd for C₂₄H₂₆ClN₃O: C, 70.66; H, 6.42; N, 10.30. Found: C,70.93; H, 6.78; N, 10.01.

Example 58

[0739] Preparation ofN-(3,4-dihydro-2H-chromen-4-yl)-5-(2,4-dimethylphenyl)-3,6-diethylpyrazin-2-amine

[0740] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine,ethylene glycol dimethyl ether, 2,4-dimethyl phenyl boronic acid andtetrakis(triphenylphosphine) palladium and making non-criticalvariations provided the title compound as a oil: ¹H NMR (300 MHz, CDCl₃)δ) 7.38, 7.22, 7.11-6.90, 5.38, 4.58, 4.31, 2.68, 2.53, 2.37, 2.26,2.14, 1.25-1.15; HRMS (FAB) calcd for C₂₅H₂₉N₃O+H 388.2389, found388.2383.

[0741] Preparation 68

[0742] Preparation of 5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one

[0743] To a solution of KH (30%, 11.44 g) in tetrahydrofuran (160 ml)under N2 was added dropwise 6,7-dihydro-1-benzothiophen-4(5H)-one (8 g)in tetrahydrofuran (40 ml). After 30 min, a triethyl borane (97 ml, 1 MTHF) solution was added dropwise over 5 min. After 10 min, iodopropanewas and the reaction stirred for 16 h. The reaction mixture was cooledto 0° C. and 1 N NaOH (250 ml) and hydrogen peroxide (12 ml, 30%) wasadded. The reaction mixture stirred for 1 h and was extracted with 400ml ethyl acetate. The organic layer was washed with saturated sodiumthiosulfate, dried MgSO₄, filtered and concentrated. MPLC chromatographyon a biotage 40 L with 4% ethyl acetate/heptane provided the titlecompound as an oil (8.21 g, 80%): ¹H NMR (300 MHz, CDCl₃) δ) 7.40, 7.07,3.15-3.01, 2.47, 2.32, 2.07-1.88, 1.53-1.30, 1.27, 0.99-0.88; HRMS (FAB)calcd for C₁₁H₁₄OS+H 195.0844, found 195.0835.

[0744] Preparation 69

[0745] Preparation of(4Z)-5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one oxime

[0746] Following the procedure for the preparation of(4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one and making non-criticalvariations provided the title compound as a oil: ¹H NMR (300 MHz, CDCl₃)δ) 7.98, 7.28, 7.15, 7.10, 3.55, 2.99-2.81, 2.21-1.83, 1.59-1.31,0.95-0.90; (MS/CI) calcd for C₁₀H₁₃NOS+H 195.3, found 195.7.

[0747] Preparation 70

[0748] Preparation ofCis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine

[0749] To a solution of sodium borohydride (4.63 g) in ethylene glycoldimethyl ether (150 ml) at 0° C. under N₂ was added titaniumtetrachloride (6.89 ml). After 5 min,(4Z)-5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one oxime (6.25 g) in 50ml of ethylene glycol dimethyl ether was added dropwise to a bluesolution. The reaction mixture was stirred at ambient temperate for 24 hand carefully quenched at 0° C. with 2 N NaOH. The aqueous layer wasextracted with methylene chloride (3×200 ml), dried MgSO₄, filtered andconcentrated. MPLC chromatography on a biotage 40 L column with 2-4%methanol/methylene chloride with 0.5% ammonium hydroxide providedCis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine (2.2 g): ¹H NMR(300 MHz, CDCl₃) δ) 7.10, 6.96, 3.92, 2.90-2.72, 1.72, 1.47-1.36, 0.98;HRMS (FAB) calcd for C₁₁H₁₇NS+H 196.1160, found 196.1164. andtrans-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine (2.68 g) as anoil: ¹H NMR (300 MHz, CDCl₃) δ) 7.10, 7.02, 3.59, 2.78, 2.07, 1.66-1.48,1.38-1.24, 0.96; HRMS (FAB) calcd for C₁₁H₁₇NS+H 196.1160, found196.1157.

[0750] Preparation 71

[0751] Preparation of3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0752] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting cis-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (300 MHz, CDCl₃) δ) 7.65, 7.05, 6.92, 5.68, 4.31, 2.97-2.80, 2.68,2.53, 2.05, 1.97, 1.71, 1.51-1.25, 0.86; HRMS (FAB) calcd forC₁₉H₂₇N₃S+H 330.2004, found 330.2001. Anal. Calcd for C₁₉H₂₇N₃S: C,69.26; H, 8.26; N, 12.75; S, 9.73. Found: C, 69.21; H, 8.28; N, 12.35.

[0753] Preparation 72

[0754] Preparation of3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0755] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting trans-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amineand making non-critical variations provided the title compound as a oil:¹H NMR (300 MHz, CDCl₃) δ) 7.66, 7.08, 6.44, 5.19, 4.46, 2.82,2.68-2.52, 2.03, 1.94, 1.78, 1.53-1.48, 1.26, 0.92; HRMS (FAB) calcd forC₁₉H₂₇N₃S+H 330.2004, found 330.1993.

[0756] Preparation 73

[0757] Preparation of5-bromo-3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0758] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (300 MHz, CDCl₃) δ) 7.06, 6.88, 5.61, 4.28, 2.97-2.80, 2.54,2.05-1.92, 1.74, 1.49-1.21, 0.87; HRMS (FAB) calcd for C₁₉H₂₆BrN₃S+H408.1109, found 408.1108. Anal. Calcd for C₁₉H₂₆BrN₃S: C, 55.88; H,6.42; N, 10.29. Found: C, 55.62; H, 6.45; N, 10.18.

[0759] Preparation 74

[0760] Preparation of5-bromo-3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0761] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (300 MHz, CDCl₃) δ7.07, 6.82, 5.12, 4.41, 2.82, 2.56, 2.15-1.71,1.68-1.40, 1.28, 0.92; HRMS (FAB) calcd for C₁₉H₂₆BrN₃S+H 408.1109,found 408.1123.

Example 59

[0762] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0763] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (300 MHz, CDCl₃) δ) 7.50, 7.32, 7.08, 6.98, 5.73, 4.43,2.98, 2.82, 2.62, 2.50, 2.10, 1.95, 1.76, 1.57-1.44, 1.42-1.18, 0.89;HRMS (FAB) calcd for C₂₅H₂₉Cl₂N₃S+H 474.1537, found 474.1544. Anal.Calcd for C₂₅H₂₉Cl₂N₃S: C, 63.28; H, 6.16; N, 8.86;. Found: C, 63.61; H,6.33; N, 8.65.

Example 60

[0764] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine

[0765] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (300 MHz, CDCl₃) δ) 7.50, 7.35-7.31, 7.11, 6.91, 5.21,4.59, 2.82, 2.64, 2.48, 2.05, 1.82, 1.43-1.35, 1.25, 1.18, 0.94; HRMS(FAB) calcd for C₂₅H₂₉Cl₂N₃S+H 474.1537, found 474.1526.

[0766] Preparation 75

[0767] Preparation of(1R,2S)-1-[(3,6-dimethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[0768] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 3-chloro-2,5-dimethylpyrazine and making non-criticalvariations provided the title compound as a oil: ¹H NMR (300 MHz, CDCl₃)δ) 7.68, 7.32-7.28, 5.59, 4.80, 3.27, 3.09, 2.92, 2.38; HRMS (FAB) calcdfor C₁₅H₁₇N₃O+H 256.1450, found 256.1460.

[0769] Preparation 76

[0770] Preparation of(1R,2S)-1-[(5-bromo-3,6-dimethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[0771] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting(1R,2S)-1-[(3,6-dimethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as a oil:¹H NMR (300 MHz, CDCl₃) δ) 7.32-7.28, 5.58, 4.92, 4.77, 3.28, 3.07,2.51, 2.38, 2.28; HRMS (FAB) calcd for C₁₅H₁₆BrN₃O+H 334.0555, found334.0557. Anal. Calcd for C₁₅H₁₆BrN₃O: C, 53.91; H, 4.83; N, 12.57.Found: C, 53.55; H, 4.88; N, 12.27.

[0772] Preparation 77

[0773] Preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[0774] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting(1R,2S)-1[(5-bromo-3,6-dimethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as a oil:¹H NMR (300 MHz, CDCl₃) δ) 7.51, 7.36-7.28, 5.66, 4.98, 4.82, 3.25,3.11, 2.75, 2.42, 2.26; HRMS (FAB) calcd for C₂₁H₁₉Cl₂N₃O+H 400.0983,found 400.0995. Anal. Calcd for C₂₁H₁₉Cl₂N₃O: C, 63.01; H, 4.78; N,10.50. Found: C, 62.86; H, 4.80; N, 10.39.

Example 61

[0775] Preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethylpyrazin-2-amine

[0776] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland methyl iodide, and making non-critical variations provided the titlecompound as a oil: ¹H NMR (300 MHz, CDCl₃) δ) 7.51, 7.43, 7.37-7.25,5.86, 5.40, 4.28, 3.43, 3.23, 3.06, 2.42, 2.25; HRMS (FAB) calcd forC₂₂H₂₁Cl₂N₃O+H 414.1140, found 414.1143. Anal. Calcd for C₂₂H₂₁Cl₂N₃O:C, 63.78; H, 5.11; N, 10.14. Found: C, 63.86; H, 5.21; N, 10.07.

Example 62

[0777] Preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethylpyrazin-2-amine

[0778] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]amino}-2,3-1H-inden-2-oland making non-critical variations provided the title compound as a oil:¹H NMR (300 MHz, CDCl₃) δ); 7.50-7.48, 7.32-7.28, 5.81, 5.48, 4.38,3.70, 3.52, 3.14, 2.41, 2.26, 1.20; HRMS (FAB) calcd for C₂₃H₂₃Cl₂N₃O+H428.1296, found 428.1288. Anal. Calcd for C₂₃H₂₃Cl₂N₃O: C, 64.49; H,5.41; N, 9.8. Found: C, 64.49; H, 5.48; N, 9.74.

Example 63

[0779] Preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethylpyrazin-2-amine

[0780] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland 2-iodopropane, and making non-critical variations provided the titlecompound as a oil: ¹H NMR (300 MHz, CDCl₃) δ) 7.50-7.46, 7.34-7.26,5.76, 5.43, 4.47, 3.72, 3.14-3.11, 2.41, 2.26, 1.20, 1.12; HRMS (FAB)calcd for C₂₄H₂₅Cl₂N₃O+H 442.1453, found 442.1441. Anal. Calcd forC₂₄H₂₅Cl₂N₃O: C, 65.16; H, 5.70; N, 9.50. Found: C, 65.33; H, 5.83; N,9.34.

[0781] Preparation 78

[0782] Preparation of 8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine

[0783] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting8-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-criticalvariations provided the title compound as a oil: ¹H NMR (300 MHz, CDCl₃)δ) 7.13, 6.73, 4.21, 3.87, 2.78-2.72, 1.88; HRMS (FAB) calcd forC₁₁H₁₅NO+H 178.1232, found 178.1232.

[0784] Preparation 79

[0785] Preparation of3,6-diethyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0786] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(300 MHz, CDCl₃) δ) 7.63, 7.22, 6.78, 5.40, 4.31, 3.71, 2.86-2.65,2.53-2.38, 1.88-1.67, 1.32, 1.21; HRMS (FAB) calcd for C₁₉H₂₅N₃O+H312.2076, found 312.2077.

[0787] Preparation 80

[0788] Preparation of5-bromo-3,6-diethyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0789] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (300 MHz, CDCl₃) δ) 7.23, 6.78, 5.32, 4.31, 3.71, 2.89-2.77,2.50-2.35, 1.81-1.65, 1.32, 1.18; HRMS (FAB) calcd for C₁₉H₂₄BrN₃O+H390.1181, found 390.1172. Anal. Calcd for C₁₉H₂₄BrN₃O: C, 58.47; H,6.20; N, 10.77. Found: C, 58.07; H, 6.13; N, 10.51.

Example 64

[0790] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine

[0791] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (300 MHz, CDCl₃) δ) 7.50, 7.34-7.22, 6.83, 5.46, 4.45,3.75, 2.94-2.79, 2.60-2.53, 1.92-1.77, 1.28-1.16; HRMS (FAB) calcd forC₂₅H₂₇Cl₂N₃O+H 456.1609, found 456.1602.

[0792] Preparation 81

[0793] Preparation of 6-methoxyindan-1-amine

[0794] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting8-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-criticalvariations provided the title compound as a oil: ¹H NMR (CDCl₃) δ1.72,2.54, 2.74, 2.90, 3.83, 4.34, 6.78, 6.91, 7.13; MS (FAB) m/z (rel.intensity) 164 (MH+, 17), 308 (8), 164 (17), 163 (7), 162 (19), 148(18), 147 (99), 146 (18), 145 (9), 121 (11), 115 (8). HRMS (FAB) calcdfor C₁₀H₁₃NO+H 164.1075, found 164.1071.

[0795] Preparation 82

[0796] Preparation of3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine

[0797] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 6-methoxyindan-1-amine and making non-critical variationsprovided the title compound as a oil: ¹H NMR (CDCl₃) δ1.31, 1.87, 2.59,2.67, 2.75, 2.87, 2.95, 3.79, 4.55, 5.75, 6.83, 7.19, 7.70; HRMS (FAB)calcd for C₁₈H₂₃N₃O+H 298.1919, found 298.1909. Anal. Calcd forC₁₈H₂₃N₃O: C, 72.70; H, 7.80; N, 14.13. Found: C, 72.19; H, 7.76; N,13.84.

[0798] Preparation 83

[0799] Preparation of5-bromo-3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine

[0800] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ1.27-1.31, 1.86, 2.58, 2.75, 2.83, 2.85, 2.97, 3.80, 4.54,5.67, 6.83-6.88, 7.20; HRMS (FAB) calcd for C₁₈H₂₂BrN₃O+H 376.1025,found 376.1020. Anal. Calcd for C₁₈H₂₂BrN₃O: C, 57.45; H, 5.89; N,11.17; Br, 21.23. Found: C, 56.15; H, 5.65; N, 10.83.

Example 65

[0801] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine

[0802] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (CDCl₃) δ1.21, 1.29, 1.94, 2.51, 2.67, 2.80, 2.92,3.01, 3.81, 4.69, 5.80, 6.86, 6.95, 7.22, 7.29-7.36, 7.51; HRMS (FAB)calcd for C₂₄H₂₅Cl₂N₃O+H 442.1453, found 442.1443.

[0803] Preparation 84

[0804] Preparation of 2-ethyl-6-methoxyindan-1-one

[0805] Following the procedure for the preparation of5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting6-methoxy 1-tetralone and ethyl iodide, and making non-criticalvariations provided the title compound as a oil: ¹H NMR (CDCl₃) δ1.02,1.55, 1.99, 2.68, 2.77, 3.27, 3.86, 7.21, 7.37; HRMS (FAB) calcd forC₁₂H₁₄O₂+H 191.1072, found 191.1075.

[0806] Preparation 85

[0807] Preparation of 2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-one oxime

[0808] Following the procedure for the preparation of(4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting2-ethyl-6-methoxyindan-1-one and making non-critical variations providedthe title compound as a oil: HRMS (FAB) calcd for C₁₂H₁₅NO₂+H 206.1181,found 206.1175. Anal. Calcd for C₁₂H₁₅NO₂: C, 70.22; H, 7.37; N, 6.82.Found: C, 69.90; H, 7.48; N, 6.64.

[0809] Preparation 86

[0810] Preparation of cis-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-amine

[0811] Following the procedure for the preparation of6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine but substituting2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-one oxime and makingnon-critical variations provided the title compound as a oil: ¹H NMR(CDCl₃) δ1.03, 1.39, 2.30, 2.63, 2.86, 3.82, 4.26, 6.77, 7.12;

[0812] Preparation 87

[0813] Preparation of3,6-diethyl-N-[(cis)-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0814] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting cis-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ0.93, 1.27-1.34, 2.58, 2.68, 3.00, 3.79, 4.44, 5.83, 6.80,6.92, 7.17, 7.68; HRMS (EI) calcd for C₂₀H₂₇N₃O 325.2154, found325.2157.

[0815] Preparation 88

[0816] Preparation of5-bromo-3,6-diethyl-N-[(cis)-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0817] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-[(cis)-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amineand making non-critical variations provided the title compound as a oil:¹H NMR (CDCl₃) δ0.93, 1.21-1.34, 2.57, 2.73, 2.82, 3.00, 3.79, 4.41,5.76, 6.82, 7.17; HRMS (FAB) calcd for C₂₀H₂₆BrN₃O+H 404.1338, found404.1317. Anal. Calcd for C₂₀H₂₆BrN₃O: C, 59.41; H, 6.48; N, 10.39; Br,19.76. Found: C, 59.05; H, 6.42; N, 10.13.

Example 66

[0818] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(cis)-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0819] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-[(cis)-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (CDCl₃) δ0.97, 1.22, 1.28, 2.52, 2.65, 2.75, 3.04,3.81, 4.57, 5.87, 6.84, 6.98, 7.18, 7.34, 7.50; HRMS (FAB) calcd forC₂₆H₂₉Cl₂N₃O+H 470.1766, found 470.1747

[0820] Preparation 89

[0821] Preparation of 5-methoxyindan-1-one oxime

[0822] Following the procedure for the preparation of(4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting5-methoxyindan-1-one and making non-critical variations provided thetitle compound as a oil: HRMS (EI) calcd for C₁₀H₁₁O₂ 177.0790, found177.0783. Anal. Calcd for C₁₀H₁₁NO₂: C, 67.78; H, 6.26; N, 7.90. Found:C, 67.73; H, 6.34; N, 7.77.

[0823] Preparation 90

[0824] Preparation of 5-methoxyindan-1-amine

[0825] Following the procedure for the preparation of6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine but substituting5-methoxyindan-1-one oxime and making non-critical variations providedthe title compound as a oil: ¹H NMR (CDCl₃) δ1.73, 2.75, 2.80, 2.94,3.82, 4.34, 6.80, 7.25; HRMS (FAB) calcd for C₁₀H₁₁NO+H 162.0919, found162.0922.

[0826] Preparation 91

[0827] Preparation of3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine

[0828] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 5-methoxyindan-1-amine and making non-critical variationsprovided the title compound as a oil: ¹H NMR (CDCl₃) δ1.31, 1.89, 2.58,2.67, 2.73, 2.91, 3.00, 3.83, 4.51, 5.69, 6.79, 6.85, 7.26, 7.69; ¹³CNMR (CDCl₃) δ11.08, 13.97, 26.04, 28.55, 30.84, 35.35, 55.79, 55.87,110.39, 113.15, 125.21, 130.10, 137.12, 140.93, 145.91, 151.82, 153.69,160.25; HRMS (FAB) calcd for C₁₈H₂₃N₃O+H 298.1919, found 298.1900. Anal.Calcd for C₁₈H₂₃N₃O: C, 72.70; H, 7.80; N, 14.13. Found: C, 72.51; H,8.00; N, 13.82.

[0829] Preparation 92

[0830] Preparation of5-bromo-3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine

[0831] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (CDCl₃) δ1.29, 1.89, 2.56, 2.70, 2.83, 2.87, 3.00, 3.83, 4.49, 5.61,6.81, 6.85, 7.23; HRMS (FAB) calcd for C₁₈H₂₂BrN₃O+H 376.1025, found376.1008.

Example 67

[0832] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine

[0833] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting5-bromo-3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (CDCl₃) δ) 1.28, 1.95, 2.51, 2.65, 2.80, 2.95, 3.02,3.85, 4.14, 4.65, 5.73, 6.82, 6.87, 7.28-7.35, 7.5; HRMS (FAB) calcd forC₂₄H₂₅Cl₂N₃O+H 442.1453, found 442.1450.

[0834] Preparation 93

[0835] Preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0836] Following the procedure for the preparation of4,5,6,7-tetrahydro-1-benzofuran-4-amine but5,6-dihydro-7H-cyclopenta[b]pyridin-7-one and making non-criticalvariations provided the title compound as a oil: ¹H NMR (300 MHz, DMSO)δ) 8.49, 7.79, 7.36, 4.65, 3.38, 3.01-2.90, 2.55, 1.93; (MS/CI) calcdfor C₈H₁₀N₂+H 135.2, found 135.2.

[0837] Preparation 94

[0838] Preparation ofN-(3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0839] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(300 MHz, CDCl₃) δ) 8.46, 7.60, 7.17, 5.37, 5.25, 3.11-2.95, 2.75-2.61,1.94-1.81, 1.36-1.26; (MS/CI) calcd for C₁₆H₂₀N₄+H 269.4, found 269.3.

[0840] Preparation 95

[0841] Preparation ofN-(5-bromo-3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0842] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substitutingN-(3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amineand making non-critical variations provided the title compound as a oil:¹H NMR (300 MHz, CDCl₃) δ) 8.47, 7.61, 7.18, 5.30, 3.05, 2.81, 2.78,1.98, 1.33-1.19; (MS/CI) calcd for C₁₆H₁₉N₄Br+H 348.3, found 347.1.

Example 68

[0843] Preparation ofN-[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0844] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substitutingN-(5-bromo-3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (300 MHz, CDCl₃) δ) 8.48, 7.62, 7.50, 7.34-7.19, 5.41,3.07-3.02, 2.75, 2.48, 1.97, 1.33, 1.17; HRMS (FAB) calcd forC₂₂H₂₂Cl₂N₄+H 413.1299, found 413.1285. Anal. Calcd for C₂₂H₂₂Cl₂N₄: C,63.93; H, 5.36; N, 13.555. Found: C, 63.70; H, 5.57; N, 13.15.

[0845] Preparation 96

[0846] Preparation of (5Z)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-oneoxime

[0847] Following the procedure for the preparation of(4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting6,7-dihydro-5H-cyclopenta[b]pyridin-5-one and making non-criticalvariations provided the title compound as a oil: ¹H NMR (400 MHz,DMSO-d₆) δ) 11.11, 8.50, 7.89, 7.27, 3.04, 2.81; HRMS (EI) calcd forC₈H₈N₂O 148.0637, found 148.0628.

[0848] Preparation 97

[0849] Preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine

[0850] To a solution of (5Z)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-oneoxime (320 mg) in methanol (20 ml) under N₂ was added nickel chloridehexahydrate. The reaction mixture was cooled to −40° C. and sodiumborohydride (817 mg) was slowly added over 30 min. The reaction mixturewas warmed to ambient temperature for 1 h and silica gel was added. Thereaction mixture was concentrated. MPLC chromatography was run using abiotage 25S column with 5-8% methanol/methylene chloride with 0.5%ammonium hydroxide to provide the title compound as an oil (197 mg,68%): ¹H NMR (400 MHz, CDCl₃) δ8.43, 7.66, 7.28, 7.15, 4.42, 3.13-3.00,2.97-2.91, 2.63-2.55, 1.81-1.72.

[0851] Preparation 98

[0852] Preparation ofN-(3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine

[0853] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ) 8.48, 7.73, 7.66, 7.14, 5.82, 4.54, 3.22-3.07, 2.79,2.70-2.57, 1.94 1.36-1.27; HRMS (FAB) calcd for C₁₆H₂₀N₄+H 269.1766,found 269.1763.

[0854] Preparation 99

[0855] Preparation ofN-(5-bromo-3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine

[0856] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substitutingN-(3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ) 8.49, 7.67, 7.17, 5.77, 4.55, 3.21, 3.09,2.85-2.75, 2.58, 1.97, 1.31-1.25; HRMS (FAB) calcd for C₁₆H₁₉BrN₄+H347.0872, found 347.0878.

Example 69

[0857] Preparation ofN-[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine

[0858] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substitutingN-(5-bromo-3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine,ethylene glycol dimethyl ether and tetrakis(triphenylphosphine)palladium and making non-critical variations provided the title compoundas a oil: ¹H NMR (400 MHz, CDCl₃) δ) 8.50, 7.73, 7.51, 7.36-7.28, 7.17,5.88, 4.67, 3.26-3.08, 2.86, 2.70, 2.51, 2.05-1.96, 1.29, 1.12; HRMS(FAB) calcd for C₂₂H₂₂Cl₂N₄+H 413.1299, found 413.1286.

[0859] Preparation 100

[0860] Preparation of 6-ethyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one

[0861] Following the procedure for the preparation of5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting6,7-dihydro-5H-cyclopenta[b]pyridin-5-one and iodoethane, and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ) 8.75, 7.86, 7.44, 3.33, 2.81, 2.64, 2.02, 1.58,1.03; HRMS (FAB) calcd for C₁₀H₁₁NO+H 162.0919, found 162.0913.

[0862] Preparation 101

[0863] Preparation of(7Z)-6-ethyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one oxime

[0864] Following the procedure for the preparation of(4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting6-ethyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, DMSO-d₆) δ) 11.21, 8.45, 7.74, 7.29, 3.27, 3.11, 2.65, 1.84,1.46, 0.85; HRMS (FAB) calcd for C₁₀H₁₂N₂O+H 177.1028, found 177.1029.

[0865] Preparation 102

[0866] Preparation of6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0867] Following the procedure for the preparation of6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine but substituting(7Z)-6-ethyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one oxime and makingnon-critical variations provided the title compound as a oil: ¹H NMR(400 MHz, CDCl₃) δ) 8.40, 7.51, 7.10, 4.30, 3.95, 3.07, 2.95, 2.74,2.50, 2.38, 2.03-1.93, 1.75, 1.57, 1.40, 1.09-0.97; HRMS (FAB) calcd forC₁₀H₁₄N₂+H 163.1235, found 163.1229.

[0868] Preparation 103

[0869] Preparation ofN-(3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0870] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (400 MHz, CDCl₃) δ)8.43, 7.68, 7.59, 7.16, 5.44, 5.19, 3.12-3.02,2.82-2.63, 1.43-1.25, 0.88; HRMS (FAB) calcd for C₁₈H₂₄N₄+H 297.2079,found 297.2080.

[0871] Preparation 104

[0872] Preparation ofN-(3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0873] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine andmaking non-critical variations provided the title compound as a oil: ¹HNMR (400 MHz, CDCl₃) δ) 8.41, 7.66, 7.58, 7.15, 5.53, 4.89, 3.15,2.71-2.57, 2.31, 2.01, 1.99, 1.65, 1.34, 1.22, 1.04; HRMS (FAB) calcdfor C₁₈H₂₄N₄+H 297.2079, found 297.2080.

[0874] Preparation 105

[0875] Preparation ofN-(5-bromo-3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0876] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substitutingN-(3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ) 8.43, 7.62, 7.19, 5.37, 5.28, 3.11, 3.08,2.87-2.69, 1.41-1.26, 0.86; HRMS (FAB) calcd for C₁₈H₂₃BrN₄+H 375.1185,found 375.1189.

[0877] Preparation 106

[0878] Preparation ofN-(5-bromo-3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0879] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substitutingN-(3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amineand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ) 8.37, 7.78, 7.31, 5.42-5.25, 3.28, 2.75-2.48,1.96, 1.62, 1.34, 1.05; HRMS (FAB) calcd for C₁₈H₂₃BrN₄+H 375.1185,found 375.1193.

Example 70

[0880] Preparation ofN-[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0881] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substitutingN-(5-bromo-3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amineand, tris(2-chloro-4-methoxyphenyl)boroxin, and making non-criticalvariations provided the title compound as a oil: ¹H NMR (400 MHz, CDCl₃)δ) 8.45, 7.61, 7.28, 7.19, 7.03, 6.90, 5.50, 5.31, 3.85, 3.14, 3.06,2.87-2.78, 2.51, 1.52, 1.34, 1.17, 0.97-0.87; HRMS (FAB) calcd forC₂₅H₂₉ClN₄O+H 437.2108, found 437.2103.

Example 71

[0882] Preparation ofN-[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine

[0883] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substitutingN-(5-bromo-3,6-diethylpyrazin-2-yl)-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amineand, tris(2-chloro-4-methoxyphenyl)boroxin, and making non-criticalvariations provided the title compound as a oil: ¹H NMR (400 MHz, CDCl₃)δ) 8.43, 7.60, 7.19, 7.01, 6.89, 5.59, 5.08, 3.85, 3.20, 2.77, 2.66,2.44, 2.06, 1.69, 1.33, 1.07; IR (diffuse reflectance) 2961, 2354 (w),2063 (w), 1947 (w), 1906 (w), 1577 (s), 1550, 1519, 1491 (s), 1461, 1428(s), 1397 (s), 1289, 1228, 1196, cm⁻¹ HRMS (FAB) calcd for C₂₅H₂₉ClN₄O+H437.2108, found 437.2109.

[0884] Preparation 107

[0885] Preparation of (+/−)-2-ethyl-2,3-dihydro-1H-inden-1-one

[0886] Following the procedure for the preparation of5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting1-tetralone and ethyl iodide, and making non-critical variationsprovided the title compound as a colorless mobile oil. IR (liq.) 2963,2933, 2875, 2860, 1712, 1610, 1588, 1475, 1464, 1327, 1296, 1278, 1205,749, 718 cm⁻¹; MS (EI) m/z 160 (M⁺); Anal. Calcd for C₁₁H₁₂O: C, 82.46;H, 7.55. Found: C, 20 82.16; H, 7.57.

[0887] Preparation 108

[0888] Preparation of 2-ethyl-2,3-dihydro-1H-inden-1-one oxime

[0889] Following the procedure for the preparation of(4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting(+/−)-2-ethyl-2,3-dihydro-1H-inden-1-one and making non-criticalvariations provided the title compound as a colorless syrup. MS (ESI+)for m/z 176.1 (M+H)⁺.

[0890] Preparation 109

[0891] Preparation of 2-ethylindan-1-amine

[0892] Following the procedure for the preparation of6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine but substituting2-ethyl-2,3-dihydro-1H-inden-1-one oxime and making non-criticalvariations provided the title compound as a colorless oil.

[0893] Preparation 110

[0894] Preparation of3,6-diethyl-N-(2-ethyl-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine

[0895] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 2-ethylindan-1-amine and making non-critical variationsprovided the title compound as a yellow oil. MS (ESI+) for m/z 296.2(M+H)⁺.

[0896] Preparation 111 and 112

[0897] Preparation of(+/−)-5-bromo-3,6-diethyl-N-[cis-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amineand(+/−)-5-bromo-3,6-diethyl-N-[trans-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0898] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting3,6-diethyl-N-(2-ethyl-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine andmaking non-critical variations provided the title compounds. Analyticaldata for(+/−)-5-bromo-3,6-diethyl-N-[cis-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine:IR (liq.) 3435, 2967, 2935, 2874, 1560, 1539, 1479, 1460, 1446, 1416,1390, 1243, 1177, 751, 731 cm⁻¹; MS (EI) m/z 373 (M⁺); Anal. Calcd forC₁₉H₂₄BrN₃: C, 60.97; H, 6.46; N, 11.23. Found: C, 61.01; H, 6.53; N,11.22. Analytical data for(+/−)-5-bromo-3,6-diethyl-N-[trans-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine:IR (liq.) 2967, 2935, 2874, 2856, 1561, 1537, 1478, 1460, 1447, 1416,1388, 1186, 1176, 1164, 746 cm⁻¹; OAMS supporting ions at: ESI+373.8; MS(EI) m/z 373 (M⁺); Anal. Calcd for C₁₉H₂₄BrN₃: C, 60.97; H, 6.46; N,11.23. Found: C, 60.97; H, 6.51; N, 11.16.

Example 72

[0899] Preparation of(+/−)-5-(2,4-dichlorophenyl)-3,6-diethyl-N-[cis-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0900] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting(+/−)-5-bromo-3,6-diethyl-N-[cis-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amineand making non-critical variations provided the title compound as alight yellow semi-solid. IR (liq.) 3452, 2965, 2934, 2874, 1589, 1566,1551, 1495, 1470, 1392, 1377, 1203, 1175, 1101, 752 cm⁻¹; OAMSsupporting ions at: ESI+439.8; HRMS (FAB) calcd for C₂₅H₂₇CL₂N₃+H₁440.1660, found 440.1648. Anal. Calcd for C₂₅H₂₇Cl₂N₃: C, 68.18; H,6.18; N, 9.54. Found: C, 68.33; H, 6.36; N, 9.30.

Example 73

[0901] Preparation of(+/−)-5-(2,4-dichlorophenyl)-3,6-diethyl-N-[trans-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[0902] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting(+/−)-5-bromo-3,6-diethyl-N-[trans-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amineand making non-critical variations provided the title compound as alight yellow semi-solid. IR (liq.) 3443, 2965, 2934, 2874, 1588, 1566,1551, 1497, 1470, 1390, 1203, 1186, 1173, 1101, 747 cm⁻¹; OAMSsupporting ions at: ESI+440.0; MS (EI) m/z 439 (M⁺); Anal. Calcd forC₂₅H₂₇Cl₂N₃: C, 68.18; H, 6.18; N, 9.54. Found: C, 68.11; H, 6.17; N,9.29.

[0903] Preparation 113

[0904] Preparation of benzyl6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

[0905] To a solution of the olefin (10.0 g, 49 mmol) in CH₂Cl₂ (250 ml,0.2M) was added MCPBA (22 g, 2.0 eq.). The reaction was stirred for 48 hand 200 ml of saturated sodium thiosulfate was added. After 20 min, thelayers were separated and the organic layer was washed with 2N NaOH(2×100 ml). The organic layer was dried MgSO₄, filtered and concentratedto provide the title compound as an oil (10.79 g, 99%): 1H NMR (300 MHz,CDCl3) δ7.35, 5.13, 3.93-3.84, 3.71, 3.43-3.38; IR (liq.) 2209 (w), 2068(w), 1958 (w), 1706 (s), 1455, 1448, 1428 (s), 1397 (s), 1364, 1327 (s),1214, 1206, 1107 (s), 848 (s), 699, cm⁻¹ Anal. Calcd for C₁₂H₁₃NO₃: C,65.74; H, 5.98; N, 6.39. Found: C, 65.45; H, 6.07; N, 5.99.

[0906] Preparation 114

[0907] Preparation of benzyl(trans)-3-amino-4-hydroxypyrrolidine-1-carboxylate

[0908] benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10.5 g) wasstirred in 200 ml of saturated ammonium hydroxide at 35° C. for 40 h.The reaction mixture was poured into 100 ml of 2 N NaOH, extractedmethylene chloride (4×200 ml), dried MgSO₄, filtered and concentrated toprovide the title compound as an oil (10.15 g, 95%): ¹H NMR (300 MHz,CDCl₃) δ) 7.34, 5.14, 3.99, 3.78, 3.37, 3.19, 1.77; HRMS (FAB) calcd forC₁₂H₁₆N₂O₃+H 237.1239, found 237.1244.

[0909] Preparation 115

[0910] Preparation of benzyl(trans)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate

[0911] Following the procedure for the preparation of benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylatebut substituting benzyl(trans)-3-amino-4-hydroxypyrrolidine-1-carboxylate and makingnon-critical variations provided the title compound as a oil: ¹H NMR(300 MHz, CDCl₃) δ) 7.78, 7.39, 6.41, 6.22, 5.18, 4.51-3.95, 3.40, 2.65,1.31-1.26; (MS/CI) calcd for C₂₀H₂₆N₄O₃+H 371.4, found 370.9.

[0912] Preparation 116

[0913] Preparation of benzyl(trans)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate

[0914] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting benzyl(trans)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylateand making non-critical variations provided the title compound as a oil:1H NMR (300 MHz, CDCl3) δ) 7.38, 5.17, 4.48. 4.38, 4.28, 4.12, 3.91,3.42, 2.86-2.78, 2.58, 1.32-1.24; HRMS (FAB) calcd for C₂₀H₂₅BrN₄O₃+H449.1189, found 449.1175.

[0915] Preparation 117

[0916] Preparation of benzyl(trans)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate

[0917] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting benzyl(trans)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylateand making non-critical variations provided the title compound as a oil:¹H NMR (300 MHz, CDCl₃) δ) 7.49-7.11, 5.97, 5.17, 4.78, 4.67, 4.33-4.26,4.16-3.96, 3.46, 2.69, 2.49, 1.46-1.24, 1.14; HRMS (FAB) calcd forC₂₆H₂₈Cl₂N₄O₃+H 515.1616, found 515.1606.

[0918] Preparation 118

[0919] Preparation of benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-[(4-nitrobenzoyl)oxy]pyrrolidine-1-carboxylate

[0920] To a solution of benzyl(trans)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate(2.93 g) in tetrahydrofuran (100 ml) was added p-nitrobenzoic acid (1.89g), triphenyl phosphine (2.23 g) and di-tert-butyl azodicarboxylate(1.95 g). The reaction mixture was heated at 40° C. for 18 h and waspoured into saturated sodium bicarbonate (200 ml). The aqueous layer wasextracted with ethyl acetate (2×200 ml), dried MgSO₄, filtered andconcentrated. MPLC chromatography on a biotage 40 M column with 15-20%ethyl acetate/heptane provided the title compound as an oil (3.19 g,84%): ¹H NMR (400 MHz, CDCl₃) δ) 8.35, 8.20, 7.49-7.22, 6.23, 5.81,5.32, 5.20, 5.05, 4.83, 4.27, 3.95-3.85, 3.51, 2.58-2.41, 1.63,1.32-1.14; (MS/CI) calcd for C₃₃H₃₁Cl₂N₅O₃+H 664.5, found 664.1.

[0921] Preparation 119

[0922] benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate

[0923] To a solution of benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-[(4-nitrobenzoyl)oxy]pyrrolidine-1-carboxylate(3.17 g) in tetrahydofuran (38 ml) and methanol (3 ml) was added LiOH(1M_((aq)), 38 ml). The reaction mixture stirred 45 min and was pouredinto saturated sodium bicarbonate (100 ml). The aqueous layer wasextracted ethyl acetate (2×200 ml), dried MgSO₄, filtered andconcentrated. MPLC chromatography on a biotage 40M column with 20-60%ethyl acetate/heptane provided the title compound as an oil (1.225 g,50%): ¹H NMR (400 MHz, CDCl₃) δ) 7.50, 7.46-7.25, 5.18, 4.99, 4.89,4.70, 4.51, 4.04, 3.75-3.59, 3.42-3.35, 2.70, 2.47, 2.19, 1.14; HRMS(FAB) calcd for C₂₆H₂₈Cl₂N₄O₃+H 515.1616, found 515.1641. Anal. Calcdfor C₂₆H₂₈Cl₂N₄O₃: C, 60.59; H, 5.48; N, 10.87. Found: C, 60.32; H,5.79; N, 10.54.

Example 74

[0924] benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0925] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylateand making non-critical variations provided the title compound as anoil: ¹H NMR (400 MHz, CDCl₃) δ) 7.49, 7.40-7.25, 5.20-5.13, 4.73, 4.10,3.98, 3.77-3.59, 3.53-3.30, 2.70, 2.46, 1.27, 1.15; HRMS (FAB) calcd forC₂₈H₃₂Cl₂N₄O₃+H 543.1929, found 543.1913. Anal. Calcd for C₂₈H₃₂Cl₂N₄O₃:C, 61.88; H, 5.93; N, 10.31. Found: C, 62.07; H, 6.14; N, 10.16.

Example 75

[0926]5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0927] To a solution of benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate(900 mg) in methylene chloride (16.5 ml) was added palladium dichloride(30 mg) and triethylamine (0.229 ml). Triethyl silane was added (2×0.395ml) over 2 h. The reaction mixture stirred 1 h and 2 ml oftrifluoroacetic acid was added. After 30 min the reaction was basifiedwith 2 N NaOH, extracted methylene chloride (3×100 ml), dried MgSO₄,filtered and concentrated. MPLC chromatography was run on a biotage 40Scolumn with 3-5% methanol/methylene chloride with 0.5% ammoniumhydroxide to provide the title compound as an oil (501 mg, 74%): ¹H NMR(400 MHz, CDCl₃) δ) 7.49, 7.33-7.26, 5.38, 4.54, 4.07, 3.68, 3.52, 3.22,2.95, 2.71, 2.46, 1.29, 1.15; HRMS (FAB) calcd for C₂₀H₂₆Cl₂N₄O+H409.1562, found 409.1567. Anal. Calcd for C₂₀H₂₆Cl₂N₄O: C, 58.68; H,6.40; N, 13.69. Found: C, 58.42; H, 6.43; N, 13.50.

Example 76

[0928]N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine

[0929] To a solution of5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine(105 mg) in methylene chloride (5 ml) under N₂ was added acetyl chloride(0.027 ml). The reaction mixture stirred for 30 min and was poured intosaturated sodium bicarbonate (20 ml), extracted methylene chloride (2×20ml), dried MgSO₄, filtered and concentrated. MPLC chromatography was runon a biotage 25 S column with 60% ethyl acetate/heptane to provide thetitle compound as an oil (79 mg, 69%): ¹H NMR (400 MHz, CDCl₃) δ) 7.50,7.34-7.26, 5.30, 5.12, 4.81, 4.19, 4.01, 3.87-3.67, 3.61-3.37, 2.72,2.48, 1.33-1.26, 1.14; HRMS (FAB) calcd for C₂₂H₂₈Cl₂N₄O₂+H 451.1667,found 451.1667.

Example 77

[0930]5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxy-1-propionylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0931] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting propionyl chloride and making non-critical variationsprovided the title compound as an oil: ¹H NMR (400 MHz, DMSO) δ) 7.71,7.50, 7.41, 6.00, 5.98, 4.68, 4.52, 4.22, 4.11, 3.85-3.39, 2.68, 2.37,2.25, 1.24-0.85; HRMS (FAB) calcd for C₂₃H₃₀Cl₂N₄O₂+H 465.1824, found465.1825.

Example 78

[0932] Preparation of methyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0933] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting methyl chloroformate and making non-critical variationsprovided the title compound as an oil: ¹H NMR (400 MHz, DMSO-d₆) δ)7.72, 7.50, 7.41, 6.03, 4.59, 4.17, 3.69, 3.56-3.50, 3.39, 2.67, 2.37,1.16, 1.09-1.02; HRMS (FAB) calcd for C₂₂H₂₈Cl₂N₄O₃+H 467.1617, found467.1621.

Example 79

[0934] Preparation of5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxy-1-(methylsulfonyl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0935] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting methanesulfonyl chloride and making non-criticalvariations provided the title compound as an oil: ¹H NMR (400 MHz,DMSO-d₆) δ) 7.72, 7.51, 7.42, 6.05, 4.62, 4.18, 3.66-3.57, 3.49, 3.38,2.92, 2.69, 2.38, 1.18, 1.10-1.05; HRMS (FAB) calcd for C₂₁H₂₈Cl₂N₄O₃S+H487.1337, found 487.1328.

Example 80

[0936] Preparation of ethyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0937] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting ethyl chloroformate and making non-critical variationsprovided the title compound as an oil: ¹H NMR (400 MHz, DMSO-d₆) δ)7.72, 7.50, 7.41, 6.04, 4.59, 4.16, 4.04, 3.70, 3.56-3.39, 2.67, 2.35,1.21-1.02; HRMS (FAB) calcd for C₂₃H₃₀Cl₂N₄O₃+H 481.1773, found481.1772. Anal. Calcd for C₂₃H₃₀Cl₂N₄O₃: C, 57.38; H, 6.28; N, 11.64.Found: C, 57.71; H, 6.55; N, 11.44.

Example 81

[0938] Preparation of(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-N,N-dimethylpyrrolidine-1-carboxamide

[0939] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting dimethylcarbamyl chloride and making non-criticalvariations provided the title compound as an oil: ¹H NMR (400 MHz,DMSO-d₆) δ) 7.72, 7.50, 7.41, 5.98, 4.52, 4.12, 4.00, 3.61-3.39, 2.74,2.68, 2.37, 1.23-1.05; HRMS (FAB) calcd for C₂₃H₃₁Cl₂N₅O₂+H 480.1933,found 480.1927.

Example 82

[0940] Preparation of(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-N,N-dimethylpyrrolidine-1-carbothioamide

[0941] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting dimethylthiocarbamyl chloride and making non-criticalvariations provided the title compound as an oil: ¹H NMR (400 MHz,CDCl₃) δ) 7.50, 7.34-7.25, 5.23, 4.78, 4.11, 3.97, 3.83, 3.74,3.56-3.45, 2.71, 2.46, 1.33-1.25, 1.14; HRMS (FAB) calcd forC₂₃H₃₁Cl₂N₅OS+H 496.1704, found 496.1691.

Example 83

[0942] Preparation of isopropyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0943] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting isopropyl chloroformate and making non-criticalvariations provided the title compound as an oil: ¹H NMR (400 MHz,CDCl₃) δ) 7.49, 7.34-7.26, 5.22, 4.95, 4.75, 4.08, 3.96, 3.73, 3.60,3.50, 3.38, 3.25, 2.71, 2.47, 1.32-1.25, 1.16; HRMS (FAB) calcd forC₂₄H₃₂Cl₂N₄O₃+H 495.1929, found 495.1909. Anal. Calcd for C₂₄H₃₂Cl₂N₄O₃:C, 58.18; H, 6.51; N, 11.31. Found: C, 58.43; H, 6.64; N, 11.25.

Example 84

[0944] Preparation of(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-N-methylpyrrolidine-1-carbothioamide

[0945] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting methyl thiocyanate and making non-critical variationsprovided the title compound as an oil: ¹H NMR (400 MHz, CDCl₃) δ) 7.50,7.35-7.25, 5.31, 4.87, 4.15-4.05, 3.88, 3.76, 3.51, 3.40, 2.70, 2.47,1.32-1.25, 1.15; IR (diffuse reflectance) 2970, 2933, 2351 (w), 2338(w), 1549 (s), 1536 (s), 1498 (s), 1467 (s), 1392 (s), 1353 (s), 1200,1122, 1101, 1058, 1048, cm⁻¹ HRMS (FAB) calcd for C₂₂H₂₉Cl₂N₅OS+H482.1548, found 482.1559.

Example 85

[0946] Preparation of5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxy-1-(morpholin-4-ylcarbonyl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0947] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting 4-morpholinecarbonyl chloride and making non-criticalvariations provided the title compound as an oil: ¹H NMR (400 MHz,CDCl₃) δ) 7.50, 7.34, 7.28, 5.23, 4.69, 4.10, 3.90, 3.80-3.68,3.58-3.28, 2.70, 2.49, 1.33-1.26, 1.16; IR (liq.) 2970 (s), 2934 (s),2874 (s), 2353 (w), 1996 (w), 1956 (w), 1642 (s), 1567 (s), 1552 (s),1500 (s), 1469 (s), 1414 (s,b), 1397 (s), 1118 (s), 1102 (s), cm⁻¹ HRMS(FAB) calcd for C₂₅H₃₃Cl₂N₅O₃+H 522.2039, found 522.2038.

Example 86

[0948] Preparation of 2-fluoroethyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0949] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting 2-fluoroethyl chloroformate and making non-criticalvariations provided the title compound as an oil: ¹H NMR (400 MHz,CDCl₃) δ) 7.49, 7.34-7.26, 5.21, 4.70-4.58, 4.56, 4.42, 4.34, 4.10,3.99, 3.75-3.30, 2.71, 2.47, 1.32-1.26, 1.15; IR (liq.) 2973 (s), 2347(b), 2181 (w), 1709 (s), 1567 (s), 1553 (s), 1500 (s), 1470 (s), 1445(s), 1426 (s), 1396 (s), 1347 (s), 1140 (s), 1103 (s), 1060 (s), cm⁻¹HRMS (FAB) calcd for C₂₃H₂₉Cl₂FN₄O₃+H 499.1679, found 499.1673. Anal.Calcd for C₂₃H₂₉Cl₂FN₄O₃: C, 55.32; H, 5.85; N, 11.22. Found: C, 55.20;H, 5.91; N, 10.95.

[0950] Preparation 120

[0951] Preparation of benzyl(3R,4R)-3-(2lambda˜5˜-triaza-1,2-dienyl)-4-[(trimethylsilyl)oxy]pyrrolidine-1-carboxylate

[0952] To benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (10.4 g,48 mmole) was added TMSN₃ (6.65 ml, 1.05 eq.) and1S,2S-(−)-[1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)]chromium(III)chloride (STREM 24-0851) (904 mg, 0.03 eq.). The reaction was stirredfor 18 h under N₂. The red oil was used as is in the next step. ¹H NMR(400 MHz, CDCl₃) δ7.18 (m, 5 H), 4.98 (s, 2 H), 3.99 (m, 1 H), 3.69 (m,1 H), 3.61-3.51 (m, 2 H), 3.31-3.05 (m, 2 H).

[0953] Preparation 121

[0954] Preparation of benzyl(3R,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate

[0955] Benzyl(3R,4R)-3-(2lambda˜5˜-triaza-1,2-dienyl)-4-[(trimethylsilyl)oxy]pyrrolidine-1-carboxylate(23.6 g) in MeOH (250 ml, 0.3M) was treated with TFA (15 ul) for 1.5 hr.Lindlar's catalyst (10 g) was added under 1 atmosphere of H₂. It wasstirred for 6 days. (Another batch of Lindlar's catalyst 5 g was addedon the 4^(th) day). The Pd catalyst was filtered through celite. Thefiltrate was concentrated, diluted with Et₂O (250 ml) and 1N HCl (250ml). The separated 1 N HCl phase was basified with NaOH (solid) to pH12. It was extracted with CH₃Cl:iPrOH (9:1 mixture 4×300 ml) and EtOAC(3×300 ml). It was dried (MgSO₄) and used as is. ¹H NMR (CDCl₃) δ3.22(m, 1 H), 3.38 (m, 2 H), 3.78 (m, 2 H), 4.02 (m, 1 H), 5.15 (s, 2 H),7.37 (m, 5 H);

[0956] Preparation 122

[0957] Preparation of benzyl (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate

[0958] A 50 ml oven-dried r.b.flask was charged with benzyl(3R,4R)-3-amino-4-hydroxypyrrolidine-1-carboxylate (4.235 g, 17.93 mmol)and dissolved in 60 ml of THF. Trifluoroacetic anhydride (2.54 ml, 17.93mmol) and TEA (3 ml, 21.52 mmol) were added sequentially at 0° C. Therxn was allowed to warm to r.t., and stirred for O/N. The reaction wasdiluted with H₂O (250 ml), extracted with 250 ml (CHCl₃:iPrOH 9:1mixture,×4), dried (MgSO₄), filtered, concentrated in vacuo.

[0959] This crude trifluoroamide product (confirmed by LC-MS) wasdissolved in 90 ml of CH₂Cl₂ (0.2M) and cooled to 0° C. under N₂followed by addition of TEA (21.52 mmol, 3 ml) and MsCl (1.63 ml, 19.72mmol). The reaction was stirred for 15 min at 0° C. and 1 hr at r.tfollowed by addition of DBU (5.39 ml, 53.79 mmol) with subsequentstirring overnight. The reaction mixture was filtered through silica andwashed with (80% EtOAc in Heptane,) 800 ml. The filtrate was collectedand concentrated.

[0960] The oxazoline was hydrolyzed by addition of K₂CO₃ (14.87 g) in 80ml MeOH/40 ml H₂O for 18 hr. It was reduced in volume and extracted with(9:1 CHCl₃:iPrOH) 200 ml×5. The combined organic solvent was dried(K₂CO₃), filtered, concentrated, purified by biotage chromatography (1%to 5% MeOH in CH₂Cl₂, 0.5% NH₄OH) to give the title compound as a solid.¹H NMR (CDCl₃) δ3.22 (m, 1 H), 3.38 (m, 2 H), 3.79 (m, 2 H), 4.02 (m, 1H), 5.15 (s, 2 H), 7.40 (m, 5 H); IR (diffuse reflectance) 3374, 2949,2316 (w), 1966 (w), 1947 (w), 1686 (s), 1450 (s), 1423 (s), 1354, 1321,1144, 1096, 1084, 765, 695, cm⁻¹ HRMS (FAB) calcd for C₁₂H₁₆N₂O₃+H237.1239, found 237.1236. Specific Rotation (25 C D)=−17 (c 0.97,chloroform).

[0961] Preparation 123

[0962] Preparation of benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate

[0963] To an 250 ml r.b-flask was sequentially added benzyl(3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (4.9714 g, 21.04mmol), chloride (3.949 g, 23.15 mmol), Pd₂(dba)₃ (10 mol %, 1.926 g),2-dicyclohexylphosphino-2′-(N,N-dimethyl amino)biphenyl (20 mol %, 1.656g), and DME (110 ml). Cs₂CO₃ (9.57 g) was then added and the reactionmixture was stirred at 80° C. for 20 hr. It was cooled, diluted withEt₂O (100 ml), poured into NaHCO₃ (80 ml), extracted with CH₂Cl₂ (150ml×3), dried (MgSO₄), and concentrated. Purification via biotagechromatography (35% EtOAc in heptane) provided the title compound. ¹HNMR (CDCl₃) δ1.28 (m, 6 H), 2.65 (m, 4 H), 3.36 (m, 1 H), 3.63 (m, 1 H),3.73 (m, 1 H), 4.00 (m, 1 H), 4.51 (m, 1 H), 4.64 (m, 1 H), 4.80 (m, 1H), 5.18 (s, 2 H), 7.38 (m, 6 H), 7.74 (d, 1H); IR (liq.) 2969, 2344(w), 1996 (w), 1952 (w), 1703 (s), 1691 (s), 1546, 1499 (s), 1449 (s),1426 (s), 1395, 1359 (s), 1175, 1133, 1095, cm⁻¹ HRMS (FAB) calcd forC₂₀H₂₆N₄O₃+H 371.2083, found 371.2089.

[0964] Preparation 124

[0965] Preparation of benzyl(3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate

[0966] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylateand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ) 7.38, 5.16, 4.91, 4.82, 4.59, 4.48, 4.59,4.48, 4.01, 3.72-3.58, 3.36-3.25, 2.81, 2.69, 2.54, 2.46, 1.31-1.23.

[0967] Preparation 125

[0968] Preparation of benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate

[0969] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting benzyl(3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylateand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ) 7.49, 7.39-7.25, 5.18, 4.99, 4.89, 4.71,4.55, 4.04, 3.75-3.58, 3.36, 2.69, 2.49, 1.30, 1.15; HRMS (FAB) calcdfor C₂₆H₂₈Cl₂N₄O₃+H 515.1616, found 515.1641.

Example 87

[0970] Preparation of benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0971] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylateand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, CDCl₃) δ) 7.49, 7.40-7.25, 5.20-5.13, 4.76, 4.11, 3.98,3.73-3.60, 3.51-3.31, 2.70, 2.47, 1.31-1.24, 1.15; IR (liq.) 2972, 2342(w), 1948 (w), 1709 (s), 1567, 1552, 1498 (s), 1470 (s), 1449 (s), 1420(s), 1397 (s), 1350, 1126, 1100 (s), 1080, cm⁻¹ HRMS (FAB) calcd forC₂₈H₃₂Cl₂N₄O₃+H 543.1929, found 543.1929. Anal. Calcd for C₂₈H₃₂Cl₂N₄O₃:C, 61.88; H, 5.93; N, 10.31. Found: C, 61.73; H, 6.08; N, 10.04.

Example 88

[0972] Preparation of5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[0973] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-aminebut substituting benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylateand making non-critical variations provided the title compound as anoil: ¹H NMR (400 MHz, CDCl₃) δ) 7.49, 7.33-7.26, 5.38, 4.54, 4.07, 3.68,3.52, 3.22, 2.95, 2.71, 2.46, 1.29, 1.15; HRMS (FAB) calcd forC₂₀H₂₆Cl₂N₄O+H 409.1562, found 409.1567. Anal. Calcd for C₂₀H₂₆Cl₂N₄O:C, 58.68; H, 6.40; N, 13.69. Found: C, 58.42; H, 6.43; N, 13.50.

Example 89

[0974] Preparation of methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[0975] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amineand methyl chloroformate, and making non-critical variations providedthe title compound as an oil: ¹H NMR (400 MHz, CDCl₃) δ) 7.49,7.34-7.26, 5.20, 4.73, 4.09, 3.95, 3.74, 3.60, 3.50, 3.39, 3.31, 3.26,2.69, 2.47, 1.32-1.25, 1.15; IR (diffuse reflectance) 2971 (s), 2350(w), 2341 (w), 2063 (w), 1940 (w), 1921 (w), 1710 (s), 1568, 1551, 1499,1466 (s), 1452 (s), 1392 (s), 1373, 1102, cm⁻¹; HRMS (FAB) calcd forC₂₂H₂₈Cl₂N₄O₃+H 467.1617, found 467.1619. Anal. Calcd for C₂₂H₂₈Cl₂N₄O₃:C, 56.54; H, 6.04; N, 11.99. Found: C, 56.64; H, 6.27; N, 11.92.

Example 90

[0976] Preparation of benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0977] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylateand 2-fluoro-1-bromo ethane, and making non-critical variations providedthe title compound as a oil: ¹H NMR (400 MHz, CDCl₃) δ) 7.49, 7.41-7.25,5.18, 4.81, 4.67, 4.55, 4.17, 4.06, 3.80-3.62, 3.39-3.29, 2.69, 2.47,1.28, 1.15; IR (diffuse reflectance) 2971, 2386 (w), 2350 (w), 2338 (w),2039 (w), 2014 (w), 1710 (s), 1699 (s,b), 1569, 1499, 1467 (s), 1450,1428, 1420, 1397, cm⁻¹; HRMS (FAB) calcd for C₂₈H₃₁Cl₂FN₄O₃+H 561.1835,found 561.1808.

Example 91

[0978] Preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine

[0979] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-aminebut substituting benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylateand making non-critical variations provided the title compound as anoil: ¹H NMR (400 MHz, CDCl₃) δ) 7.49, 7.35-7.26, 5.38, 4.68-4.53, 4.11,3.88, 3.80, 3.74, 3.46, 3.24-3.16, 2.93, 2.70, 2.62, 2.29, 2.00,1.33-1.24, 1.15; IR (liq.) 2971 (s), 2936 (s), 2874, 2359 (w), 2342 (w),1566 (s), 1552 (s), 1500 (s), 1470 (s), 1396 (s), 1200 (s), 1129 (s),1102 (s), 1046 (s), 868, cm⁻¹; HRMS (FAB) calcd for C₂₀H₂₅Cl₂FN₄O+H427.1468, found 427.1474.

Example 92

[0980] Preparation of methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0981] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amineand methyl chloroformate, and making non-critical variations providedthe title compound as an oil: ¹H NMR (400 MHz, DMSO-d₆) δ) 7.71, 7.50,7.41, 6.04, 4.61, 4.54, 4.42, 4.25, 3.78-3.70, 3.60, 3.54, 3.37, 2.65,2.37, 1.15, 1.08; IR (diffuse reflectance) 2970, 2934, 2350 (w), 2341(w), 2039 (w), 1940 (w), 1921 (w), 1710 (s), 1569, 1551, 1499, 1466 (s),1452 (s), 1393 (s), 1373, cm⁻¹; HRMS (FAB) calcd for C₂₂H₂₇Cl₂FN₄O₃+H485.1522, found 485.1541. Anal. Calcd for C₂₂H₂₇Cl₂FN₄O₃: C, 54.44; H,5.61; N, 11.54. Found: C, 54.73; H, 5.76; N, 11.46.

[0982] Preparation 126

[0983] Preparation of benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0984] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylateand 2-fluoro-1-bromo ethane, and making non-critical variations providedthe title compound as a oil: ¹H NMR (400 MHz, DMSO-d₆) δ) 7.61,7.38-7.36, 5.85, 5.08, 4.52, 4.50, 4.38, 4.22, 3.75-3.40, 2.60, 2.53,1.19-1.13; IR (liq.) 2970 (s), 2937 (s), 2340 (w), 2068 (w), 1996 (w),1954 (w), 1705 (s), 1546 (s), 1499 (s), 1448 (s), 1422 (s), 1395 (s),1351 (s), 1136 (s), 1107 (s), cm⁻¹; HRMS (FAB) calcd for C₂₂H₂₉FN₄O₃+H417.2302, found 417.2299.

[0985] Preparation 127

[0986] Preparation of3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine

[0987] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-aminebut substituting benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-(2-fluoroethoxy)pyrrolidine-1-carboxylateand making non-critical variations provided the title compound as anoil: ¹H NMR (400 MHz, CDCl₃) δ) 7.65, 5.21, 4.64, 4.53, 4.07, 3.81-3.61,3.40, 3.22, 3.14, 2.82, 2.62, 1.33-1.25; IR (liq.) 3437, 2969 (s), 2936(s), 2874, 2348 (w), 1580 (s), 1546 (s), 1498 (s), 1464, 1449 (s), 1395,1162, 1129, 1043 (s), 870, cm⁻¹; HRMS (FAB) calcd for C₁₄H₂₃FN₄O+H283.1934, found 283.1928.

[0988] Preparation 128

[0989] Preparation of methyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0990] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amineand methyl chloroformate, and making non-critical variations providedthe title compound as an oil: ¹H NMR (400 MHz, DMSO-d₆) δ) 7.61, 5.82,4.55, 4.51, 4.39, 4.19, 3.73-3.48, 2.64-2.49, 1.20-1.14; IR (diffusereflectance) 2967, 2934, 2873, 2450 (w), 2407 (w), 2350 (w), 2334 (w),2226 (w), 1699 (s), 1499, 1457 (s), 1392 (s), 1158, 1142, 768, cm⁻¹;HRMS (FAB) calcd for C₁₆H₂₅FN₄O₃+H 341.1989, found 341.1988.

[0991] Preparation 129

[0992] Preparation of methyl(3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0993] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting methyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-(2-fluoroethoxy)pyrrolidine-1-carboxylateand making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, DMSO-d₆) δ) 6.12, 4.49, 4.37, 4.21, 3.69-3.39,2.71-2.55, 1.20-1.12; IR (liq.) 2973 (s), 2957, 2068 (b), 1996, 1705(s), 1561 (s), 1541 (s), 1481 (s), 1454 (s), 1392 (s), 1191 (s), 1175,1140 (s), 1114 (s), 1048, cm⁻¹, HRMS (FAB) calcd for C₁₆H₂₄BrFN₄O₃+H419.1094, found 419.1112. Anal. Calcd for C₁₆H₂₄BrFN₄O₃: C, 45.83; H,5.77; N, 13.36. Found: C, 45.49; H, 5.81; N, 13.03.

Example 93

[0994] Preparation ofmethyl(3R,4S)-3-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0995] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting methyl(3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-(2-fluoroethoxy)pyrrolidine-1-carboxylateand tris(4-methoxy-2-methylphenyl)boroxin, and making non-criticalvariations provided the title compound as a oil: ¹H NMR (400 MHz,DMSO-d₆) δ) 7.12, 6.80, 5.12, 5.08, 4.80, 4.66, 4.54, 4.16, 3.99-3.60,3.36, 3.27, 2.70, 2.48, 2.12, 1.28; HRMS (FAB) calcd for C₂₄H₃₃FN₄O₄+H461.2564, found 461.2570.

Example 94

[0996] Preparation of methyl(3R,4S)-3-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino)-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[0997] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting methyl(3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-(2-fluoroethoxy)pyrrolidine-1-carboxylateandN-(4-{4,6-bis[2-chloro-4-(dimethylamino)phenyl]boroxin-2-yl}-3-chlorophenyl)-N,N-dimethylamine,and making non-critical variations provided the title compound as a oil:¹H NMR (400 MHz, DMSO-d₆) δ) 7.30, 7.13, 6.76, 5.85, 4.60-4.54, 4.42,4.28, 3.72-3.53, 2.94, 2.63, 2.38, 1.19-1.13, 1.06; IR (diffusereflectance) 2963 (b), 2351 (w), 2338 (w), 2054 (w), 1927 (w), 1921 (w),1710 (s), 1706 (s), 1608, 1568, 1551, 1486 (s), 1451 (s), 1392 (s),1353, cm⁻¹; HRMS (FAB) calcd for C₂₄H₃₃ClFN₅O₃+H 494.2334, found494.2340.

Example 95

[0998] Preparation of benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate

[0999] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting benzyl(3R,4S)-3-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylateand 2-chloro-4-methoxy phenyl boronic acid, and making non-criticalvariations provided the title compound as a oil: ¹H NMR (DMSO-d₆) δ)1.06, 2.35, 2.67, 3.51, 3.57, 3.62, 3.82, 4.35, 4.46, 5.08, 5.42, 5.95,6.98, 7.11, 7.24, 7.38; IR (diffuse reflectance) 2968, 2351 (w), 2339(w), 2063 (w), 1951 (w), 1700 (s,b), 1681 (s), 1568 (s), 1482 (s), 1428(s,b), 1422 (s), 1397, 1359 (s), 1287, 1229, cm⁻¹ HRMS (FAB) calcd forC₂₇H₃₁ClN₄O₄+H 511.2112, found 511.2115.

Example 96

[1000] Preparation of benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate

[1001] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylateand making non-critical variations provided the title compound as a oil:¹H NMR (DMSO-d₆) δ) 1.04, 1.16, 2.38, 2.68, 3.34, 3.40, 3.54, 3.70,3.82, 4.18, 4.62, 5.10, 5.95, 6.98, 7.10, 7.26, 7.38; IR (diffusereflectance) 2971, 2934, 2350 (w), 2338 (w), 2063 (w), 1949 (w), 1710(s), 1568, 1482 (s), 1419 (s), 1397 (s), 1348, 1287, 1228, 1096, cm⁻¹HRMS (FAB) calcd for C₂₉H₃₅ClN₄O₄+H 539.2425, found 539.2436. Anal.Calcd for C₂₉H₃₅ClN₄O₄: C, 64.61; H, 6.54; N, 10.39; Cl, 6.58. Found: C,64.30; H, 6.56; N, 10.26.

Example 97

[1002] Preparation of benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[1003] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylateand 1-bromo-2-fluoro ethane, and making non-critical variations providedthe title compound as a oil: ¹H NMR (DMSO-d6) δ) 1.07, 1.14, 2.36, 2.65,3.60, 3.72, 3.79, 3.82, 4.27, 4.42, 4254, 4.62, 5.09, 5.95, 6.98, 7.11,7.25, 7.38; IR (diffuse reflectance) 2350 (w), 2337 (w), 2058 (w), 1952(w), 1940 (w), 1710 (s), 1569, 1552, 1483 (s), 1459, 1419 (s), 1397,1353, 1287, 1228, cm⁻¹ HRMS (FAB) calcd for C₂₉H₃₄ClFN₄O₄+H 557.2330,found 557.2338. Anal. Calcd for C₂₉H₃₄ClFN₄O₄: C, 62.53; H, 6.15; N,10.06; Cl, 6.36; F, 3.41. Found: C, 62.33; H, 6.32; N, 10.07.

Example 98

[1004] Preparation of5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine

[1005] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-aminebut substituting(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylateand making non-critical variations provided the title compound as anoil: ¹H NMR (CDCl₃) δ1.15, 1.22-1.34, 2.45, 2.71, 2.89, 3.06, 3.22,3.41, 3.51, 3.65, 3.85, 4.51, 5.32, 6.88, 7.02, 7.24.

Example 99

[1006] Preparation of methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}3-4-ethoxypyrrolidine-1-carboxylate

[1007] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amineand methyl chloroformate, and making non-critical variations providedthe title compound as an oil: ¹H NMR (DMSO-d6) δ1.03-1.09, 1.16, 2.36,2.67, 3.78, 3.51, 3.60, 3.69, 3.82, 4.15, 4.62, 5.95, 6.98, 7.11, 7.26;IR (diffuse reflectance) 2965 (s,b), 2937, 2351 (w), 2338 (w), 2213 (w),2158 (w), 2059 (w), 1710 (s), 1568 (s), 1552, 1483 (s), 1456 (s), 1393(s), 1287 (s), 1228, cm⁻¹ HRMS (FAB) calcd for C₂₃H₃₀ClFN₄O₄+H 481.2018,found 481.2026. Anal. Calcd for C₂₃H₃₀ClFN₄O₄: C, 57.44; H, 6.29; N,11.65; Cl, 7.37; F, 3.95. Found: C, 57.14; H, 6.46; N, 11.37.

Example 100

[1008] Preparation of5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine

[1009] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-aminebut substituting benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylateand making non-critical variations provided the title compound as anoil: ¹H NMR (CDCl₃) δ1.15, 1.29, 2.48, 2.70, 2.90, 2.90, 3.15, 3.23,3.44, 3.85, 4.11, 4.55, 4.66, 5.32, 6.88, 7.02, 7.24.

Example 101

[1010] Preparation of methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate

[1011] Following the procedure for the preparation ofN-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-aminebut substituting5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amineand methyl chloroformate, and making non-critical variations providedthe title compound as an oil: ¹H NMR (DMSO-d6) δ) 1.08, 1.15, 2.37,2.65, 3.54, 3.60, 3.71, 3.82, 4.25, 4.43, 4.54, 5.93, 6.98, 7.10, 7.26;IR (liq.) 2972, 2068 (w), 1996 (w), 1707 (s), 1607, 1566, 1484 (s), 1454(s), 1393 (s), 1287, 1230, 1197, 1175, 1128, 1104, cm⁻¹ HRMS (FAB) calcdfor C₂₃H₃₁ClN₄O₄+H 463.2112, found 463.2104.

[1012] Preparation 130

[1013] Preparation oftrans-(+/−)-4-[(3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol

[1014] Following the procedure for the preparation of benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylatebut substituting trans-(+/−)-4-aminotetrahydrofuran-3-ol and makingnon-critical variations provided the title compound as an orange oil. IR(diffuse reflectance) 3356, 3255, 2972, 2938, 1587, 1511, 1464, 1453,1396, 1337, 1185, 1099, 1064, 965, 888 cm⁻¹; OAMS supporting ions at:ESI+238.1; MS (EI) m/z 237 (M⁺); HRMS (FAB) calcd for C₁₂H₁₉N₃O₂+H₁238.1555, found 238.1551.

[1015] Preparation 131

[1016] Preparation oftrans-(+/−)-4-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol

[1017] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substitutingtrans-(+/−)-4-[(3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol andmaking non-critical variations provided the title compound as a lightyellow solid. IR (diffuse reflectance) 3398, 2971, 2938, 1569, 1539,1490, 1466, 1447, 1413, 1397, 1251, 1232, 1054, 969, 891 cm⁻¹; OAMSsupporting ions at: ESI+315.9 & ESI−313.9; MS (EI) m/z 315 (M⁺); HRMS(FAB) calcd for C₁₂H₁₈BRN₃O₂+H₁ 316.0661, found 316.0656; Anal. Calcdfor C₁₂H₁₈BrN₃O₂: C, 45.58; H, 5.74; N, 13.29. Found: C, 45.49; H, 5.84;N, 13.14.

[1018] Preparation 132

[1019] Preparation oftrans-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-ol

[1020] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substitutingtrans-(+/−)-4-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-oland 2-methyl-4-methoxyphenylboronic acid and making non-criticalvariations provided the title compound as a light yellow solid. IR(diffuse reflectance) 3363, 1603, 1571, 1490, 1447, 1393, 1303, 1233,1208, 1177, 1170, 1103, 1059, 887, 849 cm⁻¹; OAMS supporting ions at:ESI+358.1; MS (EI) m/z 357 (M⁺); HRMS (FAB) calcd for C₂₀H₂₇N₃O₃+H₁358.2130, found 358.2142.

Example 102

[1021] Preparation oftrans-(+/−)-N-[4-ethoxytetrahydrofuran-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine

[1022] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substitutingtrans-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-oland making non-critical variations provided the title compound as alight yellow solid. IR (diffuse reflectance) 3354, 2973, 2958, 2938,1484, 1462, 1446, 1396, 1300, 1239, 1172, 1072, 1050, 1043, 885 cm⁻¹;OAMS supporting ions at: ESI+ 386.1; MS (EI) m/z 385 (M⁺); HRMS (FAB)calcd for C₂₂H₃₁N₃O₃ +H₁ 386.2443, found 386.2438. Anal. Calcd forC₂₂H₃₁N₃O₃: C, 68.54; H, 8.11; N, 10.90. Found: C, 68.38; H, 7.99; N,10.85.

[1023] Preparation 133

[1024] Preparation ofcis-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-yl4-nitrobenzoate

[1025] Following the procedure for the preparation of(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl4-nitrobenzoate but substitutingtrans-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-oland making non-critical variations provided the title compound as alight yellow semi-solid. MS (ESI+) for m/z 507.1 (M+H)⁺.

[1026] Preparation 134

[1027] Preparation ofcis-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-ol

[1028] Following the procedure for the preparation of(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol.but substitutingcis-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-yl4-nitrobenzoate and making non-critical variations provided the titlecompound as a colorless semi-solid. OAMS supporting ions at: ESI+358.2;MS (EI) m/z 357 (M⁺); HRMS (FAB) calcd for C₂₀H₂₇N₃O₃+H₁ 358.2130, found358.2125.

Example 103

[1029] Preparation ofcis-(+/−)-N-[4-ethoxytetrahydrofuran-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine.

[1030] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting ofcis-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-oland making non-critical variations provided the title compound as alight yellow solid. IR (liq.) 2972, 2935, 2874, 1609, 1564, 1481, 1395,1294, 1243, 1204, 1160, 1123, 1077, 1069, 1058 cm⁻¹; OAMS supportingions at: ESI+386.2; MS (EI) m/z 385 (M⁺); HRMS (FAB) calcd forC₂₂H₃₁N₃O₃+H₁ 386.2443, found 386.2457. Anal. Calcd for C₂₂H₃₁N₃O₃: C,68.54; H, 8.11; N, 10.90. Found: C, 68.22; H, 8.05; N, 10.76.

[1031] Preparation 135

[1032] Preparation ofcis-(+/−)-4-[(3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol

[1033] Following the procedure for the preparation of benzyl(3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylatebut substituting cis-(+/−)-4-aminotetrahydrofuran-3-ol and makingnon-critical variations provided the title compound as a light yellowamorphous solid. IR (diffuse reflectance) 3399, 3259, 3223, 3218, 3212,2969, 2867, 2847, 1582, 1546, 1493, 1465, 1160, 1066, 920 cm⁻¹; MS (EI)m/z 237 (M⁺); HRMS (FAB) calcd for C₁₂H₁₉N₃O₂+H₁ 238.1555, found238.1558.

[1034] Preparation 136

[1035] Preparation ofcis-(+/−)-4-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol

[1036] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substitutingtrans-(+/−)-4-[(3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-ol andmaking non-critical variations provided the title compound as a lightyellow solid. IR (diffuse reflectance) 3398, 2971, 2938, 1569, 1539,1490, 1466, 1447, 1413, 1397, 1251, 1232, 1054, 969, 891 cm⁻¹; OAMSsupporting ions at: ESI+ 315.9 & ESI−313.9; MS (EI) m/z 315 (M⁺); HRMS(FAB) calcd for C₁₂H₁₈BRN₃O₂+H₁ 316.0661, found 316.0656; Anal. Calcdfor C₁₂H₁₈BrN₃O₂: C, 45.58; H, 5.74; N, 13.29. Found: C, 45.49; H, 5.84;N, 13.14.

[1037] Preparation 137

[1038] Preparation ofcis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ol.

[1039] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substitutingcis-(+/−)-4-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]tetrahydrofuran-3-oland 2-chloro-4-methoxyphenylboronic acid and making non-criticalvariations provided the title compound as a light yellow amorphoussolid. IR (diffuse reflectance) 3420, 2969, 2935, 2873, 1604, 1568,1482, 1439, 1397, 1393, 1287, 1229, 1204, 1181, 1044 cm⁻¹; OAMSsupporting ions at: ESI+378.1; MS (EI) m/z 377 (M⁺); HRMS (FAB) calcdfor C₁₉H₂₄CLN₃O₃+H₁ 378.1584, found 378.1566. Anal. Calcd forC₁₉H₂₄ClN₃O₃: C, 60.39; H, 6.40; N, 11.12. Found: C, 59.97; H, 6.46; N,10.99.

Example 104

[1040] Preparation ofcis-(+/−)-5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[4-methoxytetrahydrofuran-3-yl]pyrazin-2-amine

[1041] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting ofcis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-oland iodomethane and making non-critical variations provided the titlecompound as a colorless semi-solid. IR (liq.) 2970, 2936, 2874, 1606,1566, 1483, 1441, 1397, 1287, 1230, 1203, 1182, 1126, 1076, 1049 cm⁻¹;OAMS supporting ions at: ESI+392.1; MS (EI) m/z 391 (M⁺); HRMS (FAB)calcd for C₂₀H₂₆CLN₃O₃+H₁ 392.1741, found 392.1758. Anal. Calcd forC₂₀H₂₆ClN₃O₃: C, 61.30; H, 6.69; N, 10.72. Found: C, 61.16; H, 6.47; N,10.65.

Example 105

[1042] Preparation ofcis-(+/−)-5-(2-chloro-4-methoxyphenyl)-N-[4-ethoxytetrahydrofuran-3-yl]-3,6-diethylpyrazin-2-amine

[1043] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting ofcis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-oland making non-critical variations provided the title compound as alight yellow oil. IR (liq.) 2973, 2936, 2874, 1606, 1566, 1481, 1441,1396, 1287, 1230, 1203, 1181, 1124, 1078, 1046 cm⁻¹; OAMS supportingions at: ESI+ 406.2; MS (EI) m/z 405 (M⁺); HRMS (FAB) calcd forC₂₁H₂₈CLN₃O₃ +H₁ 406.1897, found 406.1889.

Example 106

[1044] Preparation ofcis-(+/−)-5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine

[1045] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting ofcis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-oland 1-iodopropane and making non-critical variations provided the titlecompound as a light yellow oil. IR (liq.) 2967, 2936, 2875, 1606, 1566,1483, 1441, 1396, 1287, 1230, 1203, 1124, 1078, 1058, 1046 cm⁻¹; OAMSsupporting ions at: ESI+420.2; MS (EI) m/z 419 (M⁺); HRMS (FAB) calcdfor C₂₂H₃₀CLN₃O₃+H₁ 420.2054, found 420.2052. Anal. Calcd forC₂₂H₃₀ClN₃O₃: C, 62.92; H, 7.20; N, 10.01. Found: C, 62.78; H, 7.28; N,10.01.

Example 107 and 108

[1046] Preparation of5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3R,4R)-4-propoxytetrahydrofuran-3-yl]pyrazin-2-amineand5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3S,4S)-4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine

[1047] Chiral HPLC separation of a racemic sample ofcis-(+/−)-5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[4-propoxytetrahydrofuran-3-yl]pyrazin-2-amineemploying an Chiralcel OJ column eluting with 5% isopropopylalcohol/heptane (containing 0.1% diethylamine) provided the titlecompounds. Analytical data for5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3R,4R)-4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine:OAMS supporting ions at: ESI+420.2; MS (EI) m/z 419 (M³⁰ ); [α]²⁵_(D)=23 (c 1.0, methylene chloride); HRMS (FAB) calcd forC₂₂H₃₀CLN₃O₃+H₁ 420.2054, found 420.2049. Analytical data for5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3S,4S)-4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine:OAMS supporting ions at: ESI+420.2; MS (EI) m/z 419 (M⁺); [α]²⁵ _(D)=−24(c 1.0, methylene chloride); HRMS (FAB) calcd for C₂₂H₃₀CLN₃O₃+H₁420.2054, found 420.2064. Anal. Calcd for C₂₂H₃₀ClN₃O₃: C, 62.92; H,7.20; N, 10.01. Found: C, 63.00; H, 7.11; N, 9.67.

Example 109

[1048] Preparation of(+/−)-5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[cis-4-(3-fluoropropoxy)tetrahydrofuran-3-yl]pyrazin-2-amine

[1049] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting ofcis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-oland 1-bromo-3-fluoropropane and making non-critical variations providedthe title compound as a colorless semi-solid. IR (liq.) 2969, 2936,2875, 1606, 1565, 1481, 1441, 1397, 1287, 1230, 1203, 1127, 1075, 1059,1046 cm⁻¹; OAMS supporting ions at: ESI+438.2; MS (EI) m/z 437 (M⁺);HRMS (FAB) calcd for C₂₂H₂₉CLFN₃O₃+H₁ 438.1960, found 438.1965. Anal.Calcd for C₂₂H₂₉ClFN₃O₃: C, 60.34; H, 6.67; N, 9.59. Found: C, 60.31; H,6.78; N, 9.65.

[1050] Preparation 138

[1051] N-[(1E)-phenylmethylidene]-1H-imidazol-2-amine

[1052] In order to obtain the free base, 2-aminoimidazole sulfate (5.00g, 37.8 mmol) was dissolved in water (35 mL) and Na₂CO₃ (6.25 g, 59.0mmol) was added. After 20 minutes, the water was removed under reducedpressure. After the addition of ethanol (100 mL), the salts were removedvia filtration. Concentration of the filtrate gave a light brown oilthat was dissolved in ethanol (15 mL). Benzaldehyde (4.0 mL, 39.4 mmol)was added and the mixture was heated at reflux. After 2 h, the reactionwas cooled to rt and concentrated. The crude product was purified bycolumn chromatography (Biotage, 40M) with heptanes/EtOAc (1:1) to giveimpure product. Crystallization of this material from EtOAc/heptanesgave 2.37 g (first crop, 37%) and 0.78 g (second crop, 12%) of yellowsolid: ¹H NMR (400 MHz, CDCl₃) δ10.33, 9.34, 7.90, 7.48, 7.09, 7.01; IR(diffuse reflectance) 3148, 3134, 3112, 3081, 3063, 3029, 2908, 2895,2881, 1606, 1449, 1108, 753, 738, 687 cm⁻¹; HRMS (FAB) calcd forC₁₀H₉N₃+H 172.0875, found 172.0872; Anal. Calcd for C₁₀H₉N₃: C, 70.16;H, 5.30; N, 24.54, found: C, 70.02; H, 5.32; N, 24.39.

[1053] Preparation 139

[1054] N-[(1E)-phenylmethylidene]-1-propyl-1H-imidazol-2-amine

[1055] To a solution of N-[(1E)-phenylmethylidene]-1H-imidazol-2-amine(1.00 g, 5.84 mmol) in DMF (20 mL) was added KOt-Bu (0.80 g, 7.13 mmol)and 1-iodopropane (0.63 mL, 6.46 mmol). After 3.5 h, the reaction wasdiluted with water (50 mL) and extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was purified by columnchromatography (Biotage, 40M) with heptanes/EtOAc (2:1) to give 1.12 g(90%) of yellow liquid: ¹H NMR (400 MHz, CDCl₃) δ9.23, 7.94, 7.47, 7.02,6.94, 4.14, 1.83, 0.95; IR (liq.) 2966, 2935, 2876, 1612, 1576, 1509,1477, 1450, 1313, 1282, 1150, 761, 738, 716, 690 cm⁻¹; HRMS (FAB) calcdfor C₁₃H₁₅N₃+H 214.1344, found 214.1336.

[1056] Preparation 140

[1057] 1-propyl-1H-imidazol-2-amine

[1058] A mixture ofN-[(1E)-phenylmethylidene]-1-propyl-1H-imidazol-2-amine (0.92 g, 4.31mmol) and 6N HCl (25 mL) was heated at reflux for 2 h. After cooling tort, the reaction was concentrated to a residue then taken up in 2Maqueous Na₂CO₃ and extracted with CH₂Cl₂. The combined organic layerswere washed with brine, dried over Na₂SO₄, decanted, and concentrated.The crude product was purified by column chromatography (Biotage, 40M)with CH₂Cl₂/MeOH/NH₄OH (gradient, 950:47:3 to 900:90:10) to give 0.30 g(56%) of brown oil: ¹H NMR (400 MHz, CDCl₃) δ6.63, 6.52, 4.00, 3.65,1.75, 0.95; MS (ESI+) 126.7.

Example 110

[1059]5-(2,4-dichlorophenyl)-3,6-diethyl-N-(1-propyl-1H-imidazol-2-yl)pyrazin-2-amine

[1060] A mixture of 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine(0.25 g, 0.69 mmol), 1-propyl-1H-imidazol-2-amine (0.15 g, 1.2 mmol),tris(dibenzylideneacetone) dipalladium (0.032 g, 0.032 mmol),2-dicyclohexylphosphino)biphenyl (0.037 g, 0.12 mmol), and sodiumtert-butoxide (0.093 g, 0.97 mmol) in dioxane (2.0 mL) was heated at110° C. for 21 h. After cooling to rt, the reaction was diluted withsaturated aqueous NaHCO₃ and extracted with CH₂Cl₂. The combined organiclayers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated. The crude product was purified by column chromatography(Biotage, 40M) with (Biotage, 40S) with heptanes/EtOAc (3:1) to give0.076 g (27%) of dark yellow oil: ¹H NMR (400 MHz, CDCl₃) δ12.86, 7.47,7.31, 6.70, 6.55, 3.94, 2.97, 2.48, 2.97, 2.48, 1.84, 1.30, 1.21, 0.98;IR (liq.) 2968, 2934, 1599, 1556, 1549, 1509, 1460, 1422, 1402, 1384,1373, 1302, 1174, 1102, 712 cm⁻¹; HRMS (FAB) calcd for C₂₀H₂₃Cl₂N₅+H404.1408, found 404.1416.

[1061] Preparation 141

[1062] methyl amino(cyclopropyl)acetate hydrochloride

[1063] To a solution of cyclopropyl glycine (0.50 g, 4.3 mmol) in icecold MeOH (4.3 mL) was added dropwise SOCl₂ (1.3 g, 0.8 mL, 11 mmol).The ensuing mixture was stirred at 0° C. for 10 min then allowed to warmto rt. Stir at rt overnight, concentrate and dry at rt/0.5 mmHg toprovide 0.60 g (85%) of methyl amino(cyclopropyl)acetate hydrochlorideas a solid: ¹H NMR (DMSO-d6) δ0.51-0.69, 1.05-1.17, 3.36-3.39, 3.75,8.69.

[1064] Preparation 142

[1065] methyl 2-aminobutanoate hydrochloride

[1066] Following the procedure for the preparation of methylamino(cyclopropyl)acetate hydrochloride but substitutingalpha-aminobutyric acid and making non-critical variations provided thetitle compound as a solid: MS (ESI+) for C₅H₁₁NO₂ m/z 235 (2M+H)⁺.

[1067] Preparation 143

[1068] methyl{[N-(tert-butoxycarbonyl)-L-alanyl]amino}(cyclopropyl)acetate

[1069] To an ice cold solution of methyl amino(cyclopropyl)acetatehydrochloride (0.25 g, 1.5 mmol), N-Boc-L-alanine-OH (0.34 g, 1.5 mmol)in DMF (7.5 mL) containing diisopropylphenyl amine (0.58 g, 0.8 mL, 4.5mmol) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (HATU) (0.57 g, 1.5 mmol). After stirring at rt for2 days, the mixture was diluted with EtOAc and sequentially washed withsat. aq. NaHCO₃ and sat. aq. NaCl. The organic extracts were dried overMgSO₄, filtered and concentrated. Purify by biotage MPLC (90 g column,25-30% ethyl acetate/hexanes) to afford 0.39 g (78%) methyl{[N-(tert-butoxycarbonyl)-L-alanyl]amino}(cyclopropyl)acetate as asolid: ¹H NMR (CDCl₃) δ0.39-0.62, 1.28-1.39, 1.47, 3.77, 4.03-4.19,4.99, 6.66; MS (ESI+) for C₁₄H₂₄N₂O₅ m/z 301 (M+H)⁺.

[1070] Preparation 144

[1071] methyl({2-[(tert-butoxycarbonyl)amino]butanoyl}amino)(cyclopropyl)acetate

[1072] Following the procedure for the preparation of methyl{[N-(tert-butoxycarbonyl)-L-alanyl]amino}(cyclopropyl)acetate butsubstituting N-Boc-alpha-aminobutyric acid and making non-criticalvariations provided the title compound as a solid: ¹H NMR (CDCl₃)δ0.40-0.62, 0.94-0.99, 1.09-1.12, 1.46, 1.63-2.06, 3.77, 4.04, 5.02,6.54.

[1073] Preparation 145

[1074] methyl N-{2-[(tert-butoxycarbonyl)amino]butanoyl}alaninate

[1075] Following the procedure for the preparation of methyl{[N-(tert-butoxycarbonyl)-L-alanyl]amino}(cyclopropyl)acetate butsubstituting N-Boc-alpha-aminobutyric acid and methyl 2-aminobutanoatehydrochloride and making non-critical variations provided the titlecompound as a solid: ¹H NMR (CDCl₃) δ0.82-0.91, 1.24-1.38, 1.52,1.68-2.05, 3.75, 4.20, 4.52-4.59, 5.05, 6.69.

[1076] Preparation 146

[1077] methyl (L-alanylamino)(cyclopropyl)acetate hydrochloride

[1078] A solution of methyl{[N-(tert-butoxycarbonyl)-L-alanyl]amino}(cyclopropyl)-acetate (72 mg,0.24 mmol) in 4 N HCl in dioxane (1 mL) was stirred at rt for 45 min.Concentrate to afford 57 mg (100%) of methyl(L-alanylamino)(cyclopropyl)acetate hydrochloride as a solid: ¹H NMR(DMSO-d6) δ0.42-0.60, 1.21-1.26, 1.68, 3.65-3.91, 4.60, 8.17; MS (ESI+)for C₈H₁₂N₂O₂ m/z 201 (M+H)⁺.

[1079] Preparation 147

[1080] methyl [(2-aminobutanoyl)amino](cyclopropyl)acetate hydrochloride

[1081] Following the procedure for the preparation of methyl(L-alanylamino)(cyclopropyl)acetate hydrochloride but substitutingmethyl({2-[(tert-butoxycarbonyl)amino]butanoyl}amino)(cyclopropyl)acetate andmaking non-critical variations provided the title compound as a solid:¹H NMR (DMSO-d6) δ0.29-0.40, 0.88-0.94, 1.12, 1.37, 1.75-1.82, 3.57,3.62-3.79, 8.29.

[1082] Preparation 148

[1083] methyl N-(2-aminobutanoyl)alaninate hydrochloride

[1084] Following the procedure for the preparation of methyl(L-alanylamino)(cyclopropyl)acetate hydrochloride but substitutingmethyl N-{2-[(tert-butoxycarbonyl)amino]butanoyl}alaninate and makingnon-critical variations provided the title compound as a solid: ¹H NMR(DMSO-d6) δ0.86-0.92, 1.39-1.41, 1.62-1.82, 3.64, 3.92, 4.18-4.23, 8.36.8.92.

[1085] Preparation 149

[1086] 3,6-dicyclopropylpiperazine-2,5-dione

[1087] Following the procedure for the preparation of3,6-diethylpiperazine-2,5-dione but substituting cyclopropyl glycine(prepared as described in patent U.S. Pat. No. 6,191,306) and makingnon-critical variations provided the title compound as a solid. ¹H NMR(DMSO-d6) δ0.26-0.52, 1.04-1.12, 3.15-3.18, 3.24-3.27, 3.33, 8.06, 8.19.

[1088] Preparation 150

[1089] 3-cyclopropyl-6-methylpiperazine-2,5-dione

[1090] A solution of methyl (L-alanylamino)(cyclopropyl)acetatehydrochloride (230 mg, 0.97 mmol) in 7 N NH₃ in MeOH (6 mL) was heatedat reflux for 5 hr. Cool to rt and concentrate. The resulting materialwas dried at rt/0.5 mm Hg to provide 0.21 g of3-cyclopropyl-6-methylpiperazine-2,5-dione as a solid: ¹H NMR (CDCl₃)δ0.26-0.51, 1.06-1.37, 3.16-3.25, 3.50, 3.80, 4.00, 8.13.

[1091] Preparation 151

[1092] 3-cyclopropyl-6-ethylpiperazine-2,5-dione

[1093] Following the procedure for the preparation of3-cyclopropyl-6-methylpiperazine-2,5-dione but substituting methyl[(2-aminobutanoyl)amino](cyclopropyl)acetate hydrochloride and makingnon-critical variations provided the title compound as a solid: ¹H NMR(DMSO-d6) δ0.29-0.48, 0.79-1.20, 1.69, 3.20, 3.93, 8.05.

[1094] Preparation 152

[1095] 3-ethyl-6-methylpiperazine-2,5-dione

[1096] Following the procedure for the preparation of3-cyclopropyl-6-methylpiperazine-2,5-dione but substituting methylN-(2-aminobutanoyl)alaninate hydrochloride and making non-criticalvariations provided the title compound as a solid: ¹H NMR (DMSO-d6)δ0.81-0.86, 1.25-1.27, 1.64-1.76, 3.73-3.91, 7.37, 8.07-8.15.

[1097] Preparation 153

[1098] 3-chloro-2,5-dicyclopropylpyrazine

[1099] Following the procedure for the preparation of3-chloro-2,5-diethylpyrazine but substituting3,6-dicyclopropylpiperazine-2,5-dione and making non-critical variationsprovided the title compound as an oil: ¹H NMR (CDCl₃) δ0.99-1.13,1.94-2.03, 2.38-2.47; MS (ESI+) for C₁₀H₁₁N₂ m/z 195 (M+H)⁺.

[1100] Preparation 154A and 154B

[1101] 3-chloro-2-cyclopropyl-5-methylpyrazine (A) and3-chloro-5-cyclopropyl-2-methylpyrazine (B)

[1102] Following the procedure for the preparation of3-chloro-2,5-diethylpyrazine but substituting3-cyclopropyl-6-methylpiperazine-2,5-dione and making non-criticalvariations provided 3-chloro-2-cyclopropyl-5-methylpyrazine (A) and3-chloro-5-cyclopropyl-2-methylpyrazine (B) as oils. Analytical data for3-chloro-2-cyclopropyl-5-methylpyrazine (A): ¹H NMR (CDCl₃) δ1.44, 2.35,2.90, 3.07, 8.10; MS (ESI+) for C₈H₉N₂Cl m/z 169 (M+H)⁺; Analytical datafor 3-chloro-5-cyclopropyl-2-methylpyrazine (B): ¹H NMR (CDCl₃) δ1.04,2.00, 2.57, 8.10; MS (ESI+) for C₈H₉N₂Cl m/z 169 (M+H)⁺.

[1103] Preparation 155A and 155B

[1104] 3-chloro-2-cyclopropyl-5-ethylpyrazine (A) and3-chloro-5-cyclopropyl-2-ethylpyrazine (B)

[1105] Following the procedure for the preparation of3-chloro-2,5-diethylpyrazine but substituting3-cyclopropyl-6-ethylpiperazine-2,5-dione and making non-criticalvariations provided 3-chloro-2-cyclopropyl-5-methylpyrazine (A) and3-chloro-5-cyclopropyl-2-methylpyrazine (B) as oils. Analytical data for3-chloro-2-cyclopropyl-5-ethylpyrazine (A): ¹H NMR (CDCl₃) δ1.06-1.10,1.28-1.33, 2.42-2.51, 2.73-2.81, 8.18; Analytical data for3-chloro-5-cyclopropyl-2-ethylpyrazine (B): ¹H NMR (CDCl₃) δ1.04-1.08,1.24-1.39, 1.97-2.06, 2.88-2.95, 8.31.

[1106] Preparation 156A and 156B

[1107] 3-chloro-5-ethyl-2-methylpyrazine (A) and3-chloro-2-ethyl-5-methylpyrazine (B)

[1108] Following the procedure for the preparation of3-chloro-2,5-diethylpyrazine but substituting3-ethyl-6-methylpiperazine-2,5-dione and making non-critical variationsprovided a mixture of 3-chloro-5-ethyl-2-methylpyrazine (A) and3-chloro-2-ethyl-5-methylpyrazine (B) as an oil: ¹H NMR (CDCl₃)δ1.29-1.39, 2.53, 2.63, 2.77-2.99, 8.27, 8.30.

[1109] Preparation 157

[1110](1R,2S)-1-[(3,6-dicyclopropylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1111] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 3-chloro-2,5-dicyclopropylpyrazine and making non-criticalvariations provided the title compound as a solid: ¹H NMR (CDCl₃)δ0.86-0.89, 2.00, 2.89, 3.11, 4.54, 5.17, 5.42, 6.22-6.24, 7.17-7.25,7.64; MS (ESI+) for C₁₉H₂₁N₃O m/z 308 (M+H)⁺.

[1112] Preparation 158

[1113](1R,2S)-1-[(6-cyclopropyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1114] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 3-chloro-5-cyclopropyl-2-methylpyrazine and makingnon-critical variations provided the title compound as a solid: ¹H NMR(CDCl₃) δ0.95, 1.93, 2.38, 2.61, 3.09, 3.22, 4.75, 5.50, 7.30, 7.77; MS(ESI+) for C₁₇H₁₉N₃O m/z 282 (M+H)⁺.

[1115] Preparation 159

[1116](1R,2S)-1-[(3-cyclopropyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1117] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 3-chloro-2-cyclopropyl-5-methylpyrazine and makingnon-critical variations provided the title compound as a solid: ¹H NMR(CDCl₃) δ0.92-1.01, 1.25, 1.76, 2.36, 3.08, 3.24, 4.80, 5.38, 5.59,7.22-7.49, 7.64; MS (ESI+) for C₁₇H₁₉N₃O m/z 282 (M+H)⁺.

[1118] Preparation 160

[1119](1R,2S)-1-[(6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1120] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 3-chloro-5-cyclopropyl-2-ethylpyrazine and makingnon-critical variations provided the title compound as a solid: ¹H NMR(CDCl₃) δ0.92-0.95, 1.31-1.35, 1.93, 2.59-2.70, 3.03-3.10, 3.22-3.30,4.74, 4.91, 5.49-5.52, 7.28-7.32, 7.82; MS (ESI+) for C₁₈H₂₁N₃O m/z 296(M+H)⁺.

[1121] Preparation 161

[1122](1R,2S)-1-[(3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1123] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting 3-chloro-2-cyclopropyl-5-ethylpyrazine and makingnon-critical variations provided the title compound as a solid: ¹H NMR(CDCl₃) δ0.93-1.02, 1.24-1.30, 1.72-1.81, 2.61-2.68, 3.06-3.30,4.79-4.84, 5.36, 5.58, 7.24-7.35, 7.66; MS (ESI+) for C₁₈H₂₁N₃O m/z 296(M+H)⁺.

[1124] Preparation 162A and 162B

[1125](1R,2S)-1-[(6-ethyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(A) and(1R,2S)-1-[(3-ethyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(B)

[1126] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting a mixture of 3-chloro-5-ethyl-2-methylpyrazine (A) and3-chloro-2-ethyl-5-methylpyrazine (B) and making non-critical variationsprovided a mixture of the title compounds as a solid: ¹H NMR (CDCl₃)δ1.24-1.34, 2.38, 2.63-2.69, 3.04-3.10, 3.23-3.29, 4.78-4.92, 5.58-5.63,7.24-7.32, 7.68, 7.73.

[1127] Preparation 163

[1128](1S,2S)-1-[(5-bromo-3,6-dicyclopropylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1129] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting(1R,2S)-1-[(3,6-dicyclopropylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.89-1.03, 1.27-1.30, 1.71-1.75, 2.36-2.39,3.05-3.09, 3.25-3.30, 4.72-4.75, 5.45-5.46, 7.26-7.33; MS (ESI+) forC₁₉H₂₀BrN₃O m/z 386 (M+H)⁺.

[1130] Preparation 164

[1131](1R,2S)-1-[(5-bromo-6-cyclopropyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1132] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting(1R,2S)-1-[(6-cyclopropyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.99, 2.08, 2.38, 3.04, 3.25, 4.72, 4.97, 5.45,7.24-7.31; MS (ESI+) for C₁₇H₁₈BrN₃O m/z 362 (M+H)⁺.

[1133] Preparation 165

[1134](1R,2S)-1-[(5-bromo-3-cyclopropyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1135] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting(1R,2S)-1-[(3-cyclopropyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.95-1.08, 1.69-1.78, 2.49, 3.04, 3.24, 4.78,5.39, 5.58, 7.24-7.33; MS (ESI+) for C₁₇H₁₈BrN₃O m/z 360 (M+H)⁺.

[1136] Preparation 166

[1137](1R,2S)-1-[(5-bromo-6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1138] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting(1R,2S)-1-[(6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.93-1.09, 1.28-1.39, 2.35-2.43, 2.60-2.67,2.99-3.05, 3.22-3.29, 4.70, 5.04, 5.44-5.49, 7.23-7.32; MS (ESI+) forC₁₈H₂₀BrN₃O m/z 374 (M+H)⁺.

[1139] Preparation 167

[1140](1R,2S)-1-[(5-bromo-3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1141] Following the procedure for the preparation of(1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-olbut substituting(1R,2S)-1-[(3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.86-1.08, 1.23-1.30, 1.70-1.79, 2.77-2.84,3.03-3.09, 3.23-3.30, 4.77-4.81, 5.44, 5.56, 7.23-7.32; MS (ESI+) forC₁₈H₂₀BrN₃O m/z 374 (M+H)⁺.

[1142] Preparation 168

[1143](1R,2S)-1-[(5-bromo-6-ethyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(A) and(1R,2S)-1-[(5-bromo-3-ethyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(B)

[1144] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting a mixture of(1R,2S)-1-[(6-ethyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(A) and(1R,2S)-1-[(3-ethyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(B) and making non-critical variations provided a mixture of the titlecompound as a solid: ¹H NMR (CDCl₃) δ1.11-1.24, 2.26-3.16, 4.63-4.67,4.94-4.98, 5.20, 5.46-5.50, 7.12-7.30; MS (ESI+) for C₁₆H₁₈BrN₃O m/z 348(M+H)⁺.

[1145] Preparation 169

[1146](1R,2S)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1147] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olbut substituting(1S,2S)-1-[(5-bromo-3,6-dicyclopropylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.85-0.99, 1.67, 1.82, 2.48, 3.10-3.13,3.27-3.28, 4.79, 5.40, 5.42, 7.30-7.51; MS (ESI+) for C₂₅H₂₃Cl₂N₃O m/z452 (M+H)⁺.

[1148] Preparation 170

[1149](1R,2S)-1-{[6-cyclopropyl-5-(2,4-dichlorophenyl)-3-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1150] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-[(5-bromo-6-cyclopropyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.87-1.03, 1.60-1.69, 2.42, 2.71, 3.03, 3.25,4.73, 4.99, 5.53, 7.12-7.66; MS (ESI+) for C₂₃H₂₁Cl₂N₃O m/z 426 (M+H)⁺.

[1151] Preparation 171

[1152](1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1153] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-[(5-bromo-3-cyclopropyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.96-0.99, ,1.58, 1.81, 2.26, 2.85, 3.14, 3.26,4.86, 5.44, 5.63, 7.26-7.50; MS (ESI+) for C₂₃H₂₁Cl₂N₃O m/z 426 (M+H)⁺.

[1154] Preparation 172

[1155](1R,2S)-1-{[6-cyclopropyl-5-(2,4-dichlorophenyl)-3-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1156] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-[(5-bromo-6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.96-1.00, 1.26-1.32, 2.04, 2.35-2.40, 2.61-2.66,3.0-3.04, 3.22-3.27, 4.09-4.14, 4.68-4.70, 5.08, 5.45-5.48, 7.23-7.31;MS (ESI+) for C₂₄H₂₃Cl₂N₃O m/z 440 (M+H)⁺.

[1157] Preparation 173

[1158](1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-6-cyclopropyl-3-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1159] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-[(5-bromo-6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ; MS (ESI+) for C₂₃H₂₁Cl₂N₃O m/z (M+H)⁺.

[1160] Preparation 174

[1161](1R,2S)-1-({6-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3-ethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol

[1162] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-[(5-bromo-6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ; MS (ESI+) for C₂₃H₂₁Cl₂N₃O m/z (M+H)⁺.

[1163] Preparation 175

[1164](1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1165] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-[(5-bromo-3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.94-1.02, 1.14-1.19, 1.26-1.30, 1.68-1.86, 2.06,2.28-2.49, 3.08-3.32, 4.06-4.18, 4.83-4.87, 5.49, 5.62-5.66, 7.27-7.50;MS (ESI+) for C₂₄H₂₃Cl₂N₃O m/z 440(MH)⁺.

[1166] Preparation 176

[1167](1R,2S)-1-({3-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-6-ethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol

[1168] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-[(5-bromo-3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.88-1.00, 1.13-1.171.25-1.34, 1.77-1.82, 2.11,2.52-2.58, 3.08-3.12, 3.23-3.28, 4.82-4.85, 5.41, 5.60-5.62, 7.26-7.70,7.97; MS (ESI+) for C₂₆H₃₁N₅O m/z 430(MH)⁺.

[1169] Preparation 177

[1170](1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3-cyclopropyl-6-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1171] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-[(5-bromo-3-cyclopropyl-6-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.95-1.01, 1.14-1.30, 1.80-1.84, 2.52, 2.76-2.84,3.11-3.16, 3.26-3.31, 3.80-3.88, 4.12-4.17, 4.85-4.88, 5.36, 5.61-5.63,6.88-7.03, 7.21-7.46; MS (ESI+) for C₂₅H₂₆ClN₃O₂ m/z 436(MH)⁺.

[1172] Preparation 178

[1173](1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-ethyl-3-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1174] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting(1R,2S)-1-[(5-bromo-6-ethyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(A) and(1R,2S)-1-[(5-bromo-3-ethyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(B) and making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ1.06-1.09, 1.13-1.20, 2.36-2.38, 3.00-3.22, 4.76,5.57, 7.19-7.42.

[1175] Preparation 179

[1176](1R,2S)-1-{[5-(2,4-dichlorophenyl)-3-ethyl-6-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1177] Following the procedure for the preparation of(1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol butsubstituting(1R,2S)-1-[(5-bromo-6-ethyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(A) and(1R,2S)-1-[(5-bromo-3-ethyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(B) and making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ1.15-1.28, 2.36-2.52, 2.74, 3.09-3.30, 4.85,5.68, 7.28-7.68.

Example 111

[1178]3,6-dicyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[1179] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.80-1.07, 1.17-1.20, 1.67, 1.79, 3.14-3.20,3.46-3.50, 3.70-3.72, 4.35, 5.72, 5.97, 7.24-7.50; MS (ESI+) forC₂₇H₂₇Cl₂N₃O m/z 480 (M+H)⁺.

Example 112

[1180]6-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-methylpyrazin-2-amine

[1181] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[6-cyclopropyl-5-(2,4-dichlorophenyl)-3-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.75-1.13, 1.53-1.59, 2.31, 2.98-3.09, 3.35-3.40,3.57-3.65, 4.23-4.25, 5.37, 5.62, 7.12-7.42; MS (ESI+) for C₂₅H₂₅Cl₂N₃Om/z 454 (M+H)⁺.

Example 113

[1182]3-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-methylpyrazin-2-amine

[1183] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.87-1.07, 1.18-1.23, 1.82, 2.27, 3.10-3.16,3.47-3.57, 3.66-3.76, 4.40, 5.83, 5.98, 7.25-7.50; MS (ESI+) forC₂₅H₂₅Cl₂N₃O m/z 454 (M+H)⁺.

Example 114

[1184]6-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethylpyrazin-2-amine

[1185] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[6-cyclopropyl-5-(2,4-dichlorophenyl)-3-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.82-1.33, 1.58-1.71, 2.68-2.76, 3.06-3.19,3.41-3.51, 3.65-3.75, 4.32-4.36, 5.52-5.54, 5.71-5.76, 7.23-7.52; MS(ESI+) for C₂₆H₂₇Cl₂N₃O m/z 469 (M+H)⁺.

Example 115

[1186]5-(2-chloro-4-methoxyphenyl)-6-cyclopropyl-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethylpyrazin-2-amine

[1187] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-6-cyclopropyl-3-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: MS (ESI+) for C₂₇H₃₀ClN₃O₂ m/z 465 (M+H)⁺.

Example 116

[1188]6-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethylpyrazin-2-amine

[1189] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-({6-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3-ethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.81-1.19, 1.28-1.33, 2.67-2.73, 3.11-3.14,3.42-3.51, 3.65-3.73, 4.32-4.35, 5.40-5.42, 5.72-5.75, 6.497.22-7.39,8.19; MS (ESI+) for C₂₈H₃₅N₅O m/z 458 (M+H)⁺.

Example 117

[1190]3-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine

[1191] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.87-1.21, 1.58, 1.80-1.85, 2.51, 3.15-3.17,3.46-3.56, 3.66-3.76, 4.40-4.45, 5.88, 6.04, 7.21-7.34, 7.47-7.50; MS(ESI+) for C₂₆H₂₇Cl₂N₃O m/z 469 (M+H)⁺.

Example 118

[1192]3-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine

[1193] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.85-0.95, 1.16-1.34, 1.80-1.83, 2.53-2.58,3.49-3.55, 3.68-3.72, 4.39-4.42, 5.32, 5.81-5.88, 6.46, 7.24-7.28,7.51-7.53, 8.01; MS (ESI+) for C₂₈H₃₅N₅O m/z 458 (M+H)⁺.

Example 119

[1194]5-(2-chloro-4-methoxyphenyl)-3-cyclopropyl-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine

[1195] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.77-0.86, 0.97-1.23, 1.70-1.76, 2.42, 2.67-2.69,3.00-3.11, 3.38-3.45, 3.57-3.64, 3.76-3.78, 4.30-4.34, 5.73-5.84,6.78-6.92, 7.13-7.19, 7.37-7.42; MS (ESI+) for C₂₇H₃₀ClN₃O₂ m/z465(M+H)⁺.

Example 120

[1196]5-(2-chloro-4-methoxyphenyl)-3-cyclopropyl-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine

[1197] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.77-0.86, 0.97-1.23, 1.70-1.78, 2.42, 2.63-2.75,3.00-3.11, 3.58-3.64, 3.76-3.78, 4.30-4.34, 5.73-5.84, 6.76-6.93,7.13-7.19, 7.37-7.42; MS (ESI+) for C₂₇H₃₀ClN₃O₂ m/z 465 (M+H)⁺.

Example 121

[1198]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethyl-3-methylpyrazin-2-amine

[1199] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-ethyl-3-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ0.76-0.82, 1.02-1.34, 1.56-1.58, 2.24, 2.62,3.38-3.55, 3.90-3.95, 5.22, 5.50-5.54, 6.14-6.16, 6.70-6.72, 7.04-7.62;MS (ESI+) for C₂₄H₂₅Cl₂N₃O m/z 443 (M+H)⁺.

Example 122

[1200]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethyl-6-methylpyrazin-2-amine

[1201] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3-ethyl-6-methylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: MS (ESI+) for C₂₄H₂₅Cl₂N₃O m/z 443 (M+H)⁺.

[1202] Preparation 180

[1203]N-[(1R,2R)-2-azido-2,3-dihydro-1H-inden-1-yl]-3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-amine

[1204] To a solution of(1R,2S)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol(0.76 g, 1.7 mmol) in toluene (10 mL) and THF (10 mL) was added PPh₃(1.14 g, 4.57 mmol). The solution was cooled to 0° C. and HN3 (5.6 mL,6.38 mmol) and a solution of diethylazodicarboxylate (0.69 mL, 4.37mmol) in toluene (10 mL) were added. The reaction was stirred at rtovernight. The precipitates were removed by filtration and the filtratewas concentrated. Dissolve residue in 1 N HCl and EtOAc. Extract withEtOAc (3×30 mL). The aqueous phase was neutralized with sat. aq. NaHCO₃to pH 7.5 followed by a small amount of 6 N NaOH to pH 9. The aqueousphase was extracted with CH₂Cl₂ (3×30 mL). The combined organic extractswere dried over MgSO₄, filtered and concentrated. Purify by biotage MPLC(90 g column, 29-39% ethyl acetate/hexanes) to afford 0.8 g (78%) ofN-[(1R,2R)-2-azido-2,3-dihydro-1H-inden-1-yl]-3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-amineas a solid: ¹H NMR (CDCl₃) δ0.74-1.10, 1.63-1.71, 2.97-3.03, 3.36-3.42,4.09-4.13, 4.26-4.29, 5.05, 5.57, 7.25-7.53; MS (ESI+) for C₂₅H₂₂Cl₂N₆m/z 477 (M+H)⁺.

[1205] Preparation 181

[1206](1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine

[1207] To a solution ofN-[(1R,2R)-2-azido-2,3-dihydro-1H-inden-1-yl]-3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-amine(0.55 g, 1.15 mmol) in anhydrous THF (30 mL) was added PPh₃ (0.396 g,1.51 mmol). The resulting mixture was stirred at rt for 3 hr. To thesolution was added water (0.25 mL, 13.9 mmol). The reaction is thenallowed to stir overnight at rt. The mixture is concentrated, and theresulting solid is dissolved in MeOH. Purify by passage over Bioradacidic resin by applying the MeOH solution onto the resin and rinsingthe resin with MeOH. The resin was then rinsed with 5%triethylamine/MeOH solution to afford 0.52 g (75%) of(1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamineas a solid: ¹H NMR (CDCl₃) δ0.85-1.12, 1.64-1.76, 1.89, 2.68-2.82,3.31-3.39, 3.66-3.72, 5.16, 5.33, 7.28-7.53; MS (ESI+) for C₂₅H₂₄Cl₂N₄m/z 451 (M+H)⁺.

Example 123

[1208](1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N²-ethyl-2,3-dihydro-1H-indene-1,2-diamine

[1209] To a solution of(1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine(0.15 g, 0.33 mmol) in MeOH (3.3 mL) was sequentially added acetaldehyde(22 mg, 0.5 mmol) and AcOH (5 drops). This mixture was stirred for 30min before addition of NaBH₃CN (1 M solution in THF, 0.6 mL, 0.6 mmol).Stir at rt overnight. Add additional acetic acid (2 drops), acetaldehyde(29 μL, 0.5 mmol) and NaBH₃CN (1 M solution in THF, 0.6 mL, 0.6 mmol).After 2 hr, add additional acetic acid (2 drops), acetaldehyde (29 μL,0.5 mmol) and NaBH₃CN (1 M solution in THF, 0.6 mL, 0.6 mmol). After 3hr, dilute mixture with EtOAc and wash with sat. aq. NaHCO₃ and extractwith EtOAc (3×40 mL). The combined organic extracts were dried overMgSO₄, filtered and concentrated. Purify by biotage MPLC (90 g column,100% ethyl acetate) to afford 0.16 g (44%) of(1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N²-ethyl-2,3-dihydro-1H-indene-1,2-diamineas a solid: ¹H NMR (CDCl₃) δ0.84-1.05, 1.62-1.75, 2.78-2.86, 3.31-3.37,3.52, 5.22, 5.52, 7.28-7.51; MS (ESI+) for C₂₇H₂₈Cl₂N₄ m/z 479 (M+H)⁺.

Example 124

[1210]N-((1R,2R)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)acetamide

[1211] To a solution of(1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine(0.10 g, 0.22 mmol) in CHCl₃ (1 mL) at 0° C. under N₂ was addedtrichloroacetone (30 μL, 0.26 mmol). The mixture was allowed to slowlywarn to rt for 1.5 hr. The reaction was then heated at 60° C. for 1.5 h.Cool to rt, add additional trichloroacetone (10 μL) and continue heatingat 60° C. for 2 hr. The reaction was concentrated and purified bybiotage MPLC (90 g column, 80% ethyl acetate/hexanes) to afford 0.11 g(55%) ofN-((1R,2R)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)acetamideas a solid: ¹H NMR (CDCl₃) δ0.84-1.01, 1.61-1.81, 2.04, 2.80-2.86,3.58-3.64, 4.07-4.13, 4.46, 5.56, 6.56, 7.28-7.51; MS (ESI+) forC₂₇H₂₆Cl₂N₄O m/z 493 (M+H)⁺.

Example 125

[1212](1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N²-(2-methoxyethyl)-2,3-dihydro-1H-indene-1,2-diamine

[1213] To a solution of(1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine(0.10 g, 0.22 mmol) in MeOH (2 mL) containing acetic acid (2 drops) andmethoxyacetaldehye (49 mg, 0.66 mmol) was added NaBH₃CN (1 M solution inTHF, 0.8 mL, 0.8 mmol). The mixture was stirred at rt overnight. Dilutewith sat. aq. NaHCO₃ and extract ED with EtOAc (3×30 mL). The combinedorganic extracts were dried over MgSO₄, filtered and concentrated toafford an oil that was purified by biotage MPLC (90 g column, 10% ethylacetate/hexanes) to afford 0.11 g (20%) of(1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N²-(2-methoxyethyl)-2,3-dihydro-1H-indene-1,2-diamineas a solid: ¹H NMR (CDCl₃) δ0.60-1.01, 1.45-1.70, 2.83-2.99, 3.22-3.33,3.47-3.56, 5.19, 5.53, 7.11-7.42; MS (ESI+) for C₂₈H₃₀Cl₂N₄O m/z 509(M+H)⁺.

Example 126

[1214]5-(2,4-dichlorophenyl)-N-[(1S,2R)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[1215] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-aminebut substituting(1S,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland iodoethane and making non-critical variations provided the titlecompound as a solid: MS (ESI+) for C₂₅H₂₇Cl₂N₃O m/z 457 (M+H)⁺.

Example 127

[1216]5-(2,4-dichlorophenyl)-N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine

[1217] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-aminebut substituting(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland iodoethane and making non-critical variations provided the titlecompound as a solid: ¹H NMR (CDCl₃) δ0.81, 1.17-1.21, 1.30-1.34,1.51-1.59, 1.98, 3.90-3.96, 4.02-4.08, 6.71-6.73, 7.04-7.07, 7.19; MS(ESI+) for C₂₅H₂₇Cl₂N₃O m/z 457 (M+H)⁺.

Example 128

[1218]5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine

[1219] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-aminebut substituting(1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland 1-bromo-2-fluoroethane and making non-critical variations providedthe title compound as a solid: MS (ESI+) for C₂₅H₂₆Cl₂FN₃O m/z 475(M+H)⁺.

[1220] Preparation 182

[1221] (1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1222] To a solution of 2,6-dichloropyrazine (5.0 g, 34 mmol) in n-BuOH(30 mL) was added triethylamine (6.8 g, 9.4 mL, 67 mmol) and(1R,2S)-(+)-cis-1-amino-2-indanol (5.0 g, 34 mmol). The mixture washeated at 115° C. overnight. The solution was cooled to rt andconcentrated. Dissolve material in EtOAc (200 mL) and remove insolublematerial by vacuum filtration. Wash filtrate sequentially with 4 N NaOHand sat. aq. NaCl. Dry organic extract over MgSO₄, filter andconcentrate. Purify by biotage MPLC (90 g column, 10% ethylacetate/hexanes) to afford 4.85 g (57%) of(1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol as asolid: ¹H NMR (CDCl₃) δ2.83-2.87, 3.08-3.13, 3.32, 4.54, 5.11,5.28-5.31, 7.18-7.28, 7.73, 8.12; MS (ESI+) for C₁₃H₁₂ClN₃O m/z 262(M+H)⁺.

[1223] Preparation 183

[1224] methyl6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate

[1225] An autoclave was charged with(1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (1.7g, 6.5 mmol), MeOH (20 mL), triethylamine (1.1 mL, 7.8 mmol),bis(diphenylphosphino)ferrocene (21.6 mg, 39 μmol), PdCl₂(PhCN)₂ (12.5mg, 32.5 μmol) and dried, powdered 4 Å molecular sieves (2.8 g).Evacuate and charge (3×) with carbon monoxide (350 psi). Heat at 145° C.for 18 hours. Cool to rt, release pressure and remove solids byfiltration. The mixture was diluted with CH₂Cl₂ and washed with water.The organic extract was dried over MgSO₄, filtered and concentrated.Purify by biotage MPLC (90 g column, 50% ethyl acetate/hexanes) toafford 1.4 g (77%) of methyl6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylateas a solid: ¹H NMR (CDCl₃) δ2.84-2.88, 3.09-3.14, 3.85, 4.55-4.57,5.41-5.44, 7.14-7.28, 7.61-7.63, 8.30, 8.39; MS (ESI+) for C₁₅H₁₅N₃O₃m/z 286 (M+H)⁺.

[1226] Preparation 184

[1227] methyl3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate

[1228] To a solution of methyl6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate(1.0 g, 3.5 mmol) in CH₂Cl₂ (35 mL) was added N-bromsuccinimide (0.69 g,3.86 mmol). Stir at t for 2 hr. Wash the reaction with sat. aq. NaHCO₃.The organic extract was dried over MgSO₄, filtered and concentrated.Purify by biotage MPLC (90 g column, 20% ethyl acetate/hexanes) toafford 380 mg (30%) of methyl3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylateas a solid: ¹H NMR (CDCl₃) δ3.01-3.06, 3.24-3.29, 4.00, 4.75-4.78,5.45-5.46, 7.25-7.32, 7.94; MS (ESI+) for C₁₅H₁₄BrN₃O₃ m/z 386 (M+H)⁺.

[1229] Preparation 185

[1230] methyl3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate

[1231] Charge a Kimble vial with methyl3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate(0.45 g, 1.14 mmol), Pd(PPh₃)₄ (198 mg, 0.17 mmol), and2,4-dichlorophenylboronic acid (325 mg, 1.71 mmol). Flush with N₂ andadd DMF (4 mL) and 2 M Na₂CO₃ (1.1 mL). The resulting mixture was heatedat 85° C. overnight. The mixture was diluted with sat. aq. NaHCO₃.Extract with Et2O. The organic extract was dried over MgSO₄, filteredand concentrated. Purify by biotage MPLC (90 g column, 30% ethylacetate/hexanes) to afford 290 mg (59%) of methyl3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylateas a solid: ¹H NMR (CDCl₃) δ3.06-3.09, 3.27-3.32, 3.80, 4.09-4.15, 4.84,5.58, 7.28-7.49, 8.25; MS (ESI+) for C₂₁H₁₇Cl₂N₃O₃ m/z 430 (M+H)⁺.

[1232] Preparation 186

[1233] methyl5-bromo-3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate

[1234] Following the procedure for the preparation of methyl3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylatebut substituting methyl3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylateand making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ2.99-3.04, 3.20-3.25, 3.70, 3.99-4.08, 4.77,5.59-5.62, 6.11, 7.24-7.38; MS (ESI+) for C₂₁H₁₆BrCl₂N₃O₃ m/z 509(M+H)⁺.

[1235] Preparation 187

[1236] ethyl3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylate

[1237] To a solution of methyl5-bromo-3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate(0.19 g, 0.37 mmol) in MeOH (3.7 mL) was added NaOMe (60 mg, 1.1 mmol).The mixture was heated at reflux for 3 hr. Cool to rt, and dilute withEtOAc. Wash with sat. aq. NaHCO₃. Dry organic extract over MgSO₄, filterand concentrate. Purify by biotage MPLC (90 g column, 25% ethylacetate/hexanes) to afford 0.15 g (73%) of ethyl3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylateas a solid: ¹H NMR (CDCl₃) δ3.07-3.12, 3.25-3.31, 3.76, 4.04, 4.85-4.89,5.68-5.76, 7.28-7.49; MS (ESI+) for C₂₂H₁₉Cl₂N₃O₄ m/z 460 (M+H)⁺.

Example 129

[1238] methyl3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylate

[1239] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-aminebut substituting methyl3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylateand making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ1.13-0.20, 3.15, 3.55-3.58, 3.66-3.70, 3.76,4.02, 4.41, 5.75-5.79, 6.16, 7.25-7.34, 7.48, 7.59-7.61; MS (ESI+) forC₂₄H₂₃Cl₂N₃O₄ m/z 488 (M+H)⁺.

Example 130

[1240] methyl6-{[(1R,2S)-2-(acetyloxy)-2,3-dihydro-1H-inden-1-yl]amino}-3-(2,4-dichlorophenyl)-5-methoxypyrazine-2-carboxylate

[1241] Following the procedure for the preparation of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate but substituting methyl3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylateand making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ2.03, 3.10-3.143.31-3.36, 3.75, 4.05, 5.68-5.77,6.07-6.11, 7.31-7.48; MS (ESI+) for C₂₄H₂₁Cl₂N₃O₅ m/z 502 (M+H)⁺.

[1242] Preparation 186

[1243](1R,2S)-1-[(6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1244] To a solution of(1R,2S)-1-[(6-chloropyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (2 g,7.6 mmol) in MeOH (26 mL) was added a solution of NaOMe (1.3 g, 23 mmol)in MeOH (40 mL). The mixture was heated at reflux for 24 hr. AdditionalNaOMe (1.3 g) was added. Continue heating at reflux for 24 hr, and thenadd additional NaOMe (1.3 g). Continue heating at reflux for 24 hr andcool to rt. Dilute with EtOAc and was with sat. aq. NaHCO₃. The solidswere removed by filtration. Separate phases and wash organic extractwith additional sat. aq. NaHCO₃. Dry organic extracts over MgSO₄, filterand concentrate. Purify by biotage MPLC (90 g column, 25% ethylacetate/hexanes) to afford 1.4 g (71%) of(1R,2S)-1-[(6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol as anoil: ¹H NMR (CDCl₃) δ3.04-3.08, 3.23-3.29, 3.91, 4.75-4.78, 5.18,5.42-5.45, 7.25-7.34, 7.57-7.61; MS (ESI+) for C₁₄H₁₅N₃O₂ m/z 258(M+H)⁺.

[1245] Preparation 187

[1246](1R,2S)-1-[(5-bromo-6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol

[1247] Following the procedure for the preparation of methyl3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylatebut substituting methyl(1R,2S)-1-[(6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol andmaking non-critical variations provided the title compound as a solid:¹H NMR (CDCl₃) δ2.07, 3.03-3.07, 3.25-3.30, 3.98, 4.76, 5.38, 7.26-7.32,7.45; MS (ESI+) for C₁₄H₁₄BrN₃O₂ m/z 336 (M+H)⁺.

[1248] Preparation 188

[1249](1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1250] A Kimble vial was charged with(1R,2S)-1-[(5-bromo-6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol(0.55 g, 1.63 mmol), Pd₂(dba)₃ (33 mg, 35 μmol),dicyclohexyl[2-(9-phenanthryl)phenyl]phosphine (64 mg),2,4-dichlorophenylboronic acid (567 mg, 2.67 mmol), K₃PO₄ (1.13 g, 5.34mmol) and toluene (15 mL). The vial was flushed with N2, sealed andheated at 110° C. for 6 hr. Cool to rt, add additional Pd₂(dba)₃ (33 mg)and 2,4-dichlorophenylboronic acid (0.5 g, 2.7 mmol). Continue heatingovernight. Add additional Pd₂(dba)₃ (33 mg) and2,4-dichlorophenylboronic acid (0.5 g, 2.7 mmol) and continue heatingfor 5 hr. Add additional Pd₂(dba)₃ (33 mg) and 2,4-dichlorophenylboronicacid (0.5 g, 2.7 mmol) and continue heating overnight. The reaction wascooled to rt, diluted with CH₂Cl₂, washed with sat. aq NaHCO₃ and sat.aq. NaCl. Dry organic extract over MgSO₄, filter and concentrate. Purifyby biotage MPLC (90 g column, 30% ethyl acetate/hexanes) to afford 0.2 g(31%) of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olas an oil: ¹H NMR (CDCl₃) δ3.06-3.10, 3.26-3.32, 3.92, 4.79, 5.33,5.49-5.50, 7.28-7.41, 7.50, 7.74; MS (ESI+) for C₂₀H₁₇Cl₂N₃O₂ m/z 402(M+H)⁺.

[1251] Preparation 189

[1252](1R,2S)-1-{[3-bromo-5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1253] Following the procedure for the preparation of methyl3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylatebut substituting(1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ3.09-3.13, 3.29-3.34, 3.92, 4.81, 5.60-5.63,5.99, 7.33-7.42, 7.49; MS (ESI+) for C₂₀H₁₆BrCl₂N₃O₂ m/z 479 (M+H)⁺.

[1254] Preparation 190

[1255](1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxy-3-vinylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol

[1256] To a solution of(1R,2S)-1-{[3-bromo-5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol(150 mg, 0.31 mmol) in DMF (1.6 mL) is added Pd(PPh₃)₄ (7 mg, 6 μmol),and tributyl vinyl tin (114 mg, 0.36 mmol). The reaction is heated at120° C. overnight. Sat. aq. KF (15 mL) is added and the mixture isstirred at rt for 1 hr. Extract with CH₂Cl₂ (5×30 mL). The combinedorganic extracts were dried over MgSO₄, filtered and concentrated.Purify by biotage MPLC (90 g column, 15% ethyl acetate/hexanes) toafford 132 mg (38%) of(1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxy-3-vinylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-olas a solid: ¹H NMR (CDCl₃) δ3.08-3.12, 3.28-3.34, 3.93, 4.82, 5.46-5.49,5.54-5.67, 6.09-6.13, 6.77-6.84, 7.28-7.50; MS (ESI+) for C₂₀H₁₇Cl₂N₃O₂m/z 402 (M+H)⁺.

Example 131

[1257]5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-methoxy-3-vinylpyrazin-2-amine

[1258] Following the procedure for the preparation of5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-aminebut substituting(1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxy-3-vinylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-oland making non-critical variations provided the title compound as asolid: ¹H NMR (CDCl₃) δ1.11-1.14, 3.04-3.08, 3.37-3.44, 3.60-3.68, 3.84,4.28-4.30, 5.34-5.37, 5.68-5.71, 5.90-5.99, 6.66-6.73, 7.14-7.26,7.32-7.40; MS (ESI+) for C₂₄H₂₃Cl₂N₃O₂ m/z 456 (M+H)⁺.

What is claimed is:
 1. A compound of Formula I

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a prodrug thereof, wherein in Formula I, X is selected from —NR₃R₄,—OR₃, —CR₃R₅R₅, —C(O)R₃, —S(O)_(m)R₃, —NR₃C(O)R₄, or —NR₃S(O)_(m)R₄, mis 0,1 or 2; Ar is selected from aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl; R₁, R₂, and R₅ are independently selected fromhalogen, —NO₂, —CN, —R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a),—C(O)NR_(a)R_(a), —C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a),—NR_(a)S(O)_(m)R_(a), —NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a),—NR_(a)C(O)NR_(a)R_(a), —NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a),—C(S)OR_(a), or —OC(O)OR_(a); R₃ and R₄ are independently selected fromR_(a), heterocycloalkyl, substituted heterocycloalkyl, substitutedheteroaryl, substituted aryl, aryl cycloalkyl, substituted arylcycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl,aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroarylheterocycloalkyl, or substituted heteroaryl heterocycloalkyl provided atleast one of R₃ or R₄ are heteroaryl, substituted heteroaryl, arylcycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl,substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substitutedaryl heterocycloalkyl, heteroaryl heterocycloalkyl, substitutedheteroaryl heterocycloalkyl, heterocycloalkyl or substitutedheterocycloalkyl; R_(a) each is selected from H, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substitutedwith 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O),thione (═S), phenyl, heteroaryl, or heterocycloalkyl where phenyl,heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5independently taken from R_(t); and R_(t) each is selected from H,halogen, —NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl,—C(O)Nalkylalkyl, —Oalkyl, NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂,SO₂NHalkyl and SO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl,benzyl, heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryland heterocycloalkyl may be optionally substituted with alkyl orhalogen, provided that the compound is not:2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-methylpiperidin-4-yl)oxy]pyrazine2,5-dimethyl-3-(2,4-dichlorophenyl)-6-(tetrahydrofuran-3-yl)oxy]pyrazine2,5-dimethyl-3-(2,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-4-yloxy)pyrazine2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-methylpiperidin-3-yl)oxy]pyrazine2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-ethylpiperidin-3-yl)oxy]pyrazine2,5-dimethyl-3-(2,4-dichlorophenyl)-6-(1-piperidin-4-yl)oxy]pyrazine2,5-dimethyl-3-(2,4-dichlorophenyl)-6-piperidin-3-yl)oxy]pyrazine2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-ethylpyrrolidin-3-yl)oxy]pyrazine2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(1-methylpyrrolidin-3-yl)oxy]pyrazine2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(pyrrolidin-3-yl)oxy]pyrazine2,5-dimethyl-3-(2,4-dichlorophenyl)-6-[(pyridin-4-yl)oxy]pyrazine.
 2. Acompound of Formula II

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a prodrug thereof, wherein in Formula II, Ar is selected from aryl,substituted aryl, heteroaryl, or substituted heteroaryl; m is 0,1 or 2;R₁ and R₂ are independently selected from halogen, —NO₂, —CN, —R_(a),—OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a); R₃and R₄ are independently selected from R_(a), heterocycloalkyl,substituted heterocycloalkyl, substituted heteroaryl, substituted aryl,aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl,substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substitutedaryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substitutedheteroaryl heterocycloalkyl provided at least one of R₃ or R₄ areheteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted arylcycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl,aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroarylheterocycloalkyl, substituted heteroaryl heterocycloalkyl,heterocycloalkyl or substituted heterocycloalkyl; R_(a) each isindependently selected from H, alkyl, cycloalkyl, haloalkyl, aryl,heteroaryl, or heterocycloalkyl optionally substituted with 1 to 5 ofR_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O), thione (═S),phenyl, heteroaryl, or heterocycloalkyl where phenyl, heteroaryl, andheterocycloalkyl are optionally substituted with 1 to 5 independentlytaken from R_(t); and R_(t) each is independently selected from H,halogen, —NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl,—C(O)Nalkylalkyl, —Oalkyl, NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂,SO₂NHalkyl and SO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl,benzyl, heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryland heterocycloalkyl may be optionally substituted with alkyl orhalogen.
 3. A compound of Formula III

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a prodrug thereof, wherein in Formula III, Ar is selected from aryl,substituted aryl, heteroaryl, or substituted heteroaryl; m is 0,1 or 2;R₁ and R₂ are independently selected from halogen, —NO₂, —CN, —R_(a),—OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a); R₃ isselected from heteroaryl, substituted heteroaryl, aryl cycloalkyl,substituted aryl cycloalkyl, heteroaryl cycloalkyl, substitutedheteroaryl cycloalkyl, aryl heterocycloalkyl, substituted arylheterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroarylheterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl;R_(a) each is independently selected from H, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionally substitutedwith 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O),thione (═S), phenyl, heteroaryl, or heterocycloalkyl where phenyl,heteroaryl, and heterocycloalkyl are optionally substituted with 1 to 5independently taken from R_(t); and R_(t) each is independently selectedfrom H, halogen, —NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, 13C(O)Nalkylalkyl, —Oalkyl, NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂,SO₂NHalkyl and SO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl,benzyl, heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryland heterocycloalkyl may be optionally substituted with alkyl orhalogen.
 4. A compound of Formula IV

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a prodrug thereof, wherein in Formula IV, Ar is selected from aryl,substituted aryl, heteroaryl, or substituted heteroaryl; m is 0,1 or 2;R₁ and R₂ are independently selected from halogen, —NO₂, —CN, —R_(a),—OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a); R_(s)each is independently selected from halogen, —NO₂, —CN, —R_(a), —OR_(a),—S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a); R_(a)each is independently selected from H, alkyl, cycloalkyl, haloalkyl,aryl, heteroaryl, or heterocycloalkyl optionally substituted with 1 to 5of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O), thione (═S),phenyl, heteroaryl, or heterocycloalkyl where phenyl, heteroaryl, andheterocycloalkyl are optionally substituted with 1 to 5 independentlytaken from R_(t); and R_(t) each is independently selected from H,halogen, —NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl,—C(O)Nalkylalkyl, —Oalkyl, NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂,SO₂NHalkyl and SO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl,benzyl, heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryland heterocycloalkyl may be optionally substituted with alkyl orhalogen.
 5. A compound of claim 4 which is(+/−)-5-(2,4-dichlorophenyl)-3,6-diethyl-N-[cis-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine,or(+/−)-5-(2,4-dichlorophenyl)-3,6-diethyl-N-[trans-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine,or a pharmaceutically acceptable salt of either said compound.
 6. Acompound of Formula V

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a prodrug thereof, wherein in Formula V, Ar is selected from aryl,substituted aryl, heteroaryl, or substituted heteroaryl; m is 0,1 or 2;R_(s) each is independently selected from halogen, —NO₂, —CN, —R_(a),—OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a); R_(a)each is independently selected from H, alkyl, cycloalkyl, haloalkyl,aryl, heteroaryl, or heterocycloalkyl optionally substituted with 1 to 5of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O), thione (═S),phenyl, heteroaryl, or heterocycloalkyl where phenyl, heteroaryl, andheterocycloalkyl are optionally substituted with 1 to 5 independentlytaken from R_(t); and R_(t) each is independently selected from H,halogen, —NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl,—C(O)Nalkylalkyl, —Oalkyl, NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂,SO₂NHalkyl and SO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl,benzyl, heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryland heterocycloalkyl may be optionally substituted with alkyl orhalogen.
 7. A compound of claims 6 which is5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine,5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine,5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine,N-[(1R,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine,5-(2-chloro-4-methoxyphenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine,or5-[2-chloro-4-(dimethylamino)phenyl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine,or a pharmaceutically acceptable salt of any said compound.5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(prop-2-ynyloxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine.N-[(1R,2S)-2-(allyloxy)-2,3-dihydro-1H-inden-1-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine.N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine,or a pharmaceutically acceptable salt of any said compound.
 8. Acompound of Formula VI

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a prodrug thereof, wherein in Formula VI, Ar is selected from aryl,substituted aryl, heteroaryl, or substituted heteroaryl; m is 0,1 or 2;R_(s) each is independently selected from halogen, —NO₂, —CN, —R_(a),—OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —NR_(a)S(O)_(m)R_(a),—NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a), —NR_(a)C(O)NR_(a)R_(a),—NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a), —C(S)OR_(a), or —OC(O)OR_(a); R_(a)each is independently selected from H, alkyl, cycloalkyl, haloalkyl,aryl, heteroaryl, or heterocycloalkyl optionally substituted with 1 to 5of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O), thione (═S),phenyl, heteroaryl, or heterocycloalkyl where phenyl, heteroaryl, andheterocycloalkyl are optionally substituted with 1 to 5 independentlytaken from R_(t); R_(m) is C₁-C₆ alkyl substituted with from 1-2 ofhalogen, —NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl,—C(O)Nalkylalkyl, —Oalkyl, NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂,SO₂NHalkyl and SO₂Nalkylalkyl, oxo (═O), thione (═S), heterocycloalkyl,or substituted heterocycloalkyl; and R_(t) each is independentlyselected from H, halogen, —NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂,—C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl, NHalkyl, Nalkylalkyl,—S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl and SO₂Nalkylalkyl, alkyl,cycloalkyl, haloalkyl, phenyl, benzyl, heteroaryl, or heterocycloalkylwhere phenyl, benzyl heteroaryl and heterocycloalkyl may be optionallysubstituted with alkyl or halogen.
 9. A compound of claim 8 which is5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine,2-[((1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)oxy]ethanol,(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate,5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine,(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate,5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine,(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yldimethylcarbamate.5-(2,4-dimethoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine,or a pharmaceutically acceptable salt of any said compound.
 10. Acompound of Formula VII

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a prodrug thereof, wherein in Formula VII, Ar is selected from aryl,substituted aryl, heteroaryl, or substituted heteroaryl; W is O, NR_(p),or S(O)_(m); m is 0,1 or 2; R_(s) each is independently selected fromhalogen, —NO₂, —CN, —R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a),—C(O)NR_(a)R_(a), —C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a),—NR_(a)S(O)_(m)R_(a), —NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a),—NR_(a)C(O)NR_(a)R_(a), —NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a),—C(S)OR_(a), or —OC(O)OR_(a); R₁ and R₂ are independently selected fromhalogen, —NO₂, —CN, —R_(a), OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a),—C(O)NR_(a)R_(a), —C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a),—NR_(a)S(O)_(m)R_(a), —NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a),—NR_(a)C(O)NR_(a)R_(a), —NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a),—C(S)OR_(a), or —OC(O)OR_(a); R_(p) each is independently selected from—R_(a), —S(O)_(m)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —C(O)OR_(a), or —C(S)OR_(a); R_(a)each is independently selected from H, alkyl, cycloalkyl, haloalkyl,aryl, heteroaryl, or heterocycloalkyl optionally substituted with 1 to 5of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O), thione (═S),phenyl, heteroaryl, or heterocycloalkyl where phenyl, heteroaryl, andheterocycloalkyl are optionally substituted with 1 to 5 independentlytaken from R_(t); and R_(t) each is independently selected from H,halogen, —NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl,—C(O)Nalkylalkyl, —Oalkyl, NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂,SO₂NHalkyl and SO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl,benzyl, heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryland heterocycloalkyl may be optionally substituted with alkyl orhalogen.
 11. A compound of Formula VIII

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a prodrug thereof, wherein in Formula VIII, Ar is selected from aryl,substituted aryl, heteroaryl, or substituted heteroaryl; W is O, NR_(p),or S(O)_(m); m is 0,1 or 2; R_(s) each is independently selected fromhalogen, —NO₂, —CN, —R_(a), —OR_(a), —S(O)_(m)R_(a), —NR_(a)R_(a),—C(O)NR_(a)R_(a), —C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a),—NR_(a)S(O)_(m)R_(a), —NR_(a)C(O)OR_(a), —OC(O)NR_(a)R_(a),—NR_(a)C(O)NR_(a)R_(a), —NR_(a)C(S)NR_(a)R_(a), —C(O)OR_(a),—C(S)OR_(a), or —OC(O)OR_(a); R_(p) is independently selected from—R_(a), —S(O)_(m)R_(a), —C(O)NR_(a)R_(a),—C(S)NR_(a)R_(a)—S(O)_(m)NR_(a)R_(a), —C(O)OR_(a), or —C(S)OR_(a); R_(a)each is independently selected from H, alkyl, cycloalkyl, haloalkyl,aryl, heteroaryl, or heterocycloalkyl optionally substituted with 1 to 5of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t), oxo (═O), thione (═S),phenyl, heteroaryl, or heterocycloalkyl where phenyl, heteroaryl, andheterocycloalkyl are optionally substituted with 1 to 5 independentlytaken from R_(t); and R_(t) each is independently selected from H,halogen, —NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl,—C(O)Nalkylalkyl, —Oalkyl, NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂,SO₂NHalkyl and SO₂Nalkylalkyl, alkyl, cycloalkyl, haloalkyl, phenyl,benzyl, heteroaryl, or heterocycloalkyl where phenyl, benzyl heteroaryland heterocycloalkyl may be optionally substituted with alkyl orhalogen.
 12. A compound of claim 11 which is5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxy-1-propionylpyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine,ethyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate,benzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate,methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate,methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate,benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate,cis-(+/−)-5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine,or a pharmaceutically acceptable salt thereof.
 13. A compound of FormulaIX

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof,or a prodrug thereof, wherein in Formula IX, Ar is selected from aryl,substituted aryl, heteroaryl, or substituted heteroaryl; m is 0,1 or 2;Y=O or S R_(m) is C₁-C₆ alkyl substituted with from 1-2 of halogen,—NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂, —C(O)—NHalkyl, —C(O)Nalkylalkyl,—Oalkyl, NHalkyl, Nalkylalkyl, —S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl andSO₂Nalkylalkyl, oxo (═O), thione (═S), heterocycloalkyl, or substitutedheterocycloalkyl; R_(a) each is independently selected from H, alkyl,cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocycloalkyl optionallysubstituted with 1 to 5 of R_(t), —OR_(t), —S(O)_(m)R_(t), NR_(t)R_(t),oxo (═O), thione (═S), phenyl, heteroaryl, or heterocycloalkyl wherephenyl, heteroaryl, and heterocycloalkyl are optionally substituted with1 to 5 independently taken from R_(t); and R_(t) each is independentlyselected from H, halogen, —NO₂, —NH₂, —OH, —SH, —CN, —C(O)NH₂,—C(O)—NHalkyl, —C(O)Nalkylalkyl, —Oalkyl, NHalkyl, Nalkylalkyl,—S(O)_(m)alkyl, SO₂NH₂, SO₂NHalkyl and SO₂Nalkylalkyl, alkyl,cycloalkyl, haloalkyl, phenyl, benzyl, heteroaryl, or heterocycloalkylwhere phenyl, benzyl heteroaryl and heterocycloalkyl may be optionallysubstituted with alkyl or halogen.
 14. A compound of claim 13 which isbenzyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate,methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-fluoroethoxy)pyrrolidine-1-carboxylate,benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate,methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate,methyl(3S,4R)-3-(acetyloxy)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}pyrrolidine-1-carboxylate,methyl(3S,4R)-3-(acetyloxy)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}pyrrolidine-1-carboxylate,ethyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate,or ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate,or a pharmaceutically acceptable salt of any said compound.
 15. Acompound of claim 1 wherein, in Formula I, X is NR3R4.
 16. A compound ofclaim 15 wherein in Formula I one of R3 or R4 is aryl cycloalkyl orheteroaryl cycloalkyl.
 17. A compound of claim 16 wherein in Formula Ione of R3 or R4 is aryl cycloalkyl or heteroaryl cycloalkyl and thepoint of attachment is the cycloalkyl ring.
 18. A compound of claim 17wherein in Formula I R3 is aryl cycloalkyl and R4 is hydrogen, or R4 isaryl cycloalkyl and R3 is hydrogen.
 19. A compound of claim 15 whereinin Formula I R3 is heterocycloalkyl and R4 is hydrogen, or R4 isheterocycloalkyl and R3 is hydrogen.
 20. A compound of claim 15 whereinin Formula I R3 is hydrogen and R4 is substituted aryl cycloalkyl orsubstituted heteroaryl cycloalkyl and the point of attachment is thecycloalkyl ring, or R4 is hydrogen and R3 is substituted aryl cycloalkylor substituted heteroaryl cycloalkyl and the point of attachment is thecycloalkyl ring.
 21. A compound of claim 20 wherein, in the substitutedaryl cycloalkyl or substituted heteroaryl cycloalkyl, the substituent iseither alkyl or alkoxy and is on the cycloalkyl ring.
 22. A compound ofclaim 15 wherein one of R3 or R4 is substituted heterocycloalkyl wherethe substituent is either alkyl or alkoxy.
 23. A compound of claim 22wherein in the substituted heterocycloalkyl the absolute stereochemistryof the ring substituent is either (R,R), (R,S), (S,R), or (S,S).
 24. Acompound of claim 21 wherein one of R3 or R4 is substituted arylcycloalkyl where the substituent is either alkyl or alkoxy and is on thecycloalkyl ring and the absolute stereochemistry of the ring substituentis either (R,R), (R,S), (S,R), or (S,S).
 25. A compound of claim 21wherein R3 is 2-substituted-1-indanyl and R4 is hydrogen.
 26. A compoundof claim 25 wherein R3 is 2-alkoxy-1-indanyl and R4 is hydrogen;
 27. Acompound of claim 26 wherein R3 is 2(S)-alkoxy-1(R)-indanyl and R4 ishydrogen;
 28. A compound of claim 22 wherein R3 is4-substituted-3-pyrrolidinyl and R4 is hydrogen;
 29. A compound of claim28 wherein R3 is 4-alkoxy-3-pyrrolidinyl and R4 is hydrogen.
 30. Acompound of claim 29 wherein R3 is4(S)-alkoxy-3(R)-pyrrolidinyl-1-carboxylate and R4 is hydrogen.
 31. Acompound of claim 1 which is:5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2R)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-methoxyethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-propoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine;5-(2,4-dimethoxyphenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine;5-[2-chloro-4-(dimethylamino)phenyl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1yl]-3,6-diethylpyrazin-2-amine;5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-N-(2,3-dihydro-1H-inden-1-yl)-3,6-dimethylpyrazin-2-amine;N-(2,3-dihydro-1H-inden-1-yl)-5-(4-methoxy-2-methylphenyl)-3,6-dimethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine;5-(4-methoxy-2-methylphenyl)-3,6-dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine;N-[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]isoquinolin-1-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(3-ethyl-6-methylpyridin-2-yl)pyrazin-2-amine;5-(2,4-dichlorophenyl)-N-(4,6-dimethylpyridin-2-yl)-3,6-diethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(cis)-5-ethyl-4,5,6,7-tetrahydro-1-benzofuran-4-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(cis)-5-ethyl-4,5,6,7-tetrahydro-1-benzofuran-4-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-N-(3,4-dihydro-2H-thiochromen-4-yl)-3,6-diethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine;2-(2,4-dichlorophenyl)-3,6-diethyl-5-(1,2,3,4-tetrahydronaphthalen-1-yloxy)pyrazine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine;5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2R) and(1S,2S)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2R)and(1S,2S)-2-ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-3,6-diethylpyrazin-2-amine;cis-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;(cis)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(cis)-2-ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl]-3,6-diethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Cis-5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Trans-5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Cis-5-ethyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Trans-5-ethyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine;5-(2-chloro-4-methylphenyl)-N-(3,4-dihydro-2H-chromen-4-yl)-3,6-diethylpyrazin-2-amine;N-(3,4-dihydro-2H-chromen-4-yl)-5-(2,4-dimethylphenyl)-3,6-diethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[Trans-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-isopropoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(cis)-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(5-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine;N-[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine;N-[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine;N-[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine;N-[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]-6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine;(+/−)-5-(2,4-dichlorophenyl)-3,6-diethyl-N-[cis-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;(+/−)-5-(2,4-dichlorophenyl)-3,6-diethyl-N-[trans-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;benzyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate;5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine;N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine;methyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate;5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxy-1-(methylsulfonyl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine;(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-N,N-dimethylpyrrolidine-1-carboxamide;(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-N,N-dimethylpyrrolidine-1-carbothioamide;isopropyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate;(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-N-methylpyrrolidine-1-carbothioamide;5-(2,4-dichlorophenyl)-N-[(cis)-4-ethoxy-1-(morpholin-4-ylcarbonyl)pyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine;2-fluoroethyl(cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate;5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine;methyl(3R,4S)-3-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;methyl(3R,4S)-3-({5-[2-chloro-4-(dimethylamino)phenyl]-3,6-diethylpyrazin-2-yl}amino)-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate;5-(2-chloro-4-methoxyphenyl)-N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethylpyrazin-2-amine;5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3R,4S)-4-(2-fluoroethoxy)pyrrolidin-3-yl]pyrazin-2-amine;trans-(+/−)-N-[4-ethoxytetrahydrofuran-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine;cis-(+/−)-N-[4-ethoxytetrahydrofuran-3-yl]-3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-amine;cis-(+/−)-5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[4-methoxytetrahydrofuran-3-yl]pyrazin-2-amine;cis-(+/−)-5-(2-chloro-4-methoxyphenyl)-N-[4-ethoxytetrahydrofuran-3-yl]-3,6-diethylpyrazin-2-amine;5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3S,4S)-4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine;5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(3S,4S)-4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine;(+/−)-5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[cis-4-(3-fluoropropoxy)tetrahydrofuran-3-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(1-propyl-1H-imidazol-2-yl)pyrazin-2-amine;3,6-dicyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;6-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-methylpyrazin-2-amine;3-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-methylpyrazin-2-amine;6-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethylpyrazin-2-amine;5-(2-chloro-4-methoxyphenyl)-6-cyclopropyl-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethylpyrazin-2-amine;6-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethylpyrazin-2-amine;3-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine;3-cyclopropyl-5-[6-(dimethylamino)-4-methylpyridin-3-yl]-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine;5-(2-chloro-4-methoxyphenyl)-3-cyclopropyl-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine;5-(2-chloro-4-methoxyphenyl)-3-cyclopropyl-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethyl-3-methylpyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethyl-6-methylpyrazin-2-amine;(1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N²-ethyl-2,3-dihydro-1H-indene-1,2-diamine;N-((1R,2R)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)acetamide;(1R,2R)-N¹-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N²-(2-methoxyethyl)-2,3-dihydro-1H-indene-1,2-diamine;5-(2,4-dichlorophenyl)-N-[(1S,2R)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;methyl3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylate;methyl6-{[(1R,2S)-2-(acetyloxy)-2,3-dihydro-1H-inden-1-yl]amino}-3-(2,4-dichlorophenyl)-5-methoxypyrazine-2-carboxylate;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-methoxy-3-vinylpyrazin-2-amine;methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-propoxypyrrolidine-1-carboxylate;methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)pyrrolidine-1-carboxylate;methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)pyrrolidine-1-carboxylate;methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-propoxypyrrolidine-1-carboxylate;methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(propionyloxy)pyrrolidine-1-carboxylate;methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(propionyloxy)pyrrolidine-1-carboxylate;methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(propionylamino)pyrrolidine-1-carboxylate;methyl(3S,4R)-3-(acetylamino)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}pyrrolidine-1-carboxylate;methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(ethylamino)pyrrolidine-1-carboxylate;methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(propylamino)pyrrolidine-1-carboxylate;O-methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carbothioate;O-methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carbothioate;O-methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)pyrrolidine-1-carbothioate;pyridin-2-ylmethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;pyridin-3-ylmethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;pyridin-4-ylmethyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;2-piperidin-1-ylethyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;2-morpholin-4-ylethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;2-morpholin-4-ylethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(propionyloxy)pyrrolidine-1-carboxylat;2-(dimethylamino)ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)pyrrolidine-1-carboxylate;2-pyrrolidin-1-ylethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)pyrrolidine-1-carboxylate;2-(1H-imidazol-1-yl)ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;2-(methylamino)ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;2-aminoethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;2-hydroxyethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;2-methoxyethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;2-(2-oxopyrrolidin-1-yl)ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate;2-(2-oxopyridin-1(2H)-yl)ethyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate;(3S,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidin-2-one;(3S,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxy-1-methylpyrrolidin-2-one;(3S,4S)-1-benzyl-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-2-fluoroethoxy)pyrrolidin-2-one;(3R,4R)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-3-(2-fluoroethoxy)pyrrolidin-2-one;(3R,4R)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-3-(2-fluoroethoxy)-1-methylpyrrolidin-2-one;(3R,4R)-1-benzyl-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-3-(2-fluoroethoxy)pyrrolidin-2-one;5-(2,4-dichlorophenyl)-3,6-diethyl-N-(1-ethyl-1H-imidazol-2-yl)pyrazin-2-amine;ethyl(2S,3S)-3-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-2,3-dihydrofuro[2,3-b]pyridine-2-carboxylate;(2S,3S)-N-[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]-2-(ethoxymethyl)-2,3-dihydrofuro[2,3-b]pyridin-3-amine;(2R,3S)-N-[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]-2-ethyl-2,3-dihydrofuro[2,3-b]pyridin-3-amine;(2R,3S)-N-[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]-2-propyl-2,3-dihydrofuro[2,3-b]pyridin-3-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(2R)-2-(ethoxymethyl)pyrrolidin-1-yl]-3,6-diethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(2R)-2-(propoxymethyl)pyrrolidin-1-yl]pyrazin-2-amine;5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-{(2R)-2-[(2-fluoroethoxy)methyl]pyrrolidin-1-yl}pyrazin-2-amine;5-(2-chloro-4-methoxyphenyl)-N-[(2R)-2-(ethoxymethyl)pyrrolidin-1-yl]-3,6-diethylpyrazin-2-amine;5-(2-chloro-4-methoxyphenyl)-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]-3,6-bis(methoxymethyl)pyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]-3,6-bis(methoxymethyl)pyrazin-2-amine;methyl(3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-bis(methoxymethyl)pyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;methyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-bis(methoxymethyl)pyrazin-2-yl]amino}-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate;5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(3-fluoropropoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1R,2S)-2-(3-fluoropropoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylhydroxyacetate;(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylhydroxyacetate;(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylmethoxyacetate;(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylmethoxyacetate;N-[(1R,2S)-2-(2-aminoethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-amine;N-[(1R,2S)-2-(2-aminoethoxy)-2,3-dihydro-1H-inden-1-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine;(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylglycinate;(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylglycinate;5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-{(1R,2S)-2-[2-(methylamino)ethoxy]-2,3-dihydro-1H-inden-1-yl}pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-{(1R,2S)-2-[2-(methylamino)ethoxy]-2,3-dihydro-1H-inden-1-yl}pyrazin-2-amine;(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylN-methylglycinate;(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylN-methylglycinate;5-(2-chloro-4-methoxyphenyl)-N-{(1R,2S)-2-[2-(dimethylamino)ethoxy]-2,3-dihydro-1H-inden-1-yl}-3,6-diethylpyrazin-2-amine;5-(2,4-dichlorophenyl)-N-{(1R,2S)-2-[2-(dimethylamino)ethoxy]-2,3-dihydro-1H-inden-1-yl}-3,6-diethylpyrazin-2-amine;(1R,2S)-1-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylN,N-dimethylglycinate;(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylN,N-dimethylglycinate;5-(2-chloro-4-methoxyphenyl)-3,6-diethyl-N-{(1R,2S)-2-[2-(methylamino)ethoxy]-2,3-dihydro-1H-inden-1-yl}pyrazin-2-amine;(1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylmethylcarbamate;5-(4-chloro-2-methoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;5-(3,5-dichloropyridin-2-yl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;5-(3-chloro-5-methoxypyridin-2-yl)-3,6-diethyl-N-[(1R,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;(1R,2S)-1-{[5-(4-chloro-2-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate;(1R,2S)-1-{[5-(3,5-dichloropyridin-2-yl)-3,6-diethylpyrazin-2-yl]amino}-1H-inden-2-ylacetate;(1R,2S)-1-{[5-(3-chloro-5-methoxypyridin-2-yl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ylacetate5-(4-chloro-2-methoxyphenyl)-3,6-diethyl-N-[(1R,2S)-2-(3-fluoropropoxy)-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine;(3R,4R)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ylacetate;(3R,4R)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ylacetate;(3R,4R)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ylpropionate;(3R,4R)-4-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ylpropionate;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(3R,4R)-4-propoxytetrahydrofuran-3-yl]pyrazin-2-amine;5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(3R,4R)-4-(3-fluoropropoxy)tetrahydrofuran-3-yl]pyrazin-2-amine;(3S,4R)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(2-fluoroethoxy)dihydrofuran-2(3H)-one;(3S,4R)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxydihydrofuran-2(3H)-one;(3R,4S)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-5-oxotetrahydrofuran-3-ylacetate;(3R,4S)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-5-oxotetrahydrofuran-3-ylpropionate; (3S,4R)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-propoxydihydrofuran-2(3H)-one;(3S,4R)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-(3-fluoropropoxy)dihydrofuran-2(3H)-one;(1R,2S)-N-[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]-N′-ethyl-2,3-dihydro-1H-indene-1,2-diamine;N-((1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)acetamide;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-dimethoxypyrazin-2-amine;3-cyclopropyl-5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-methoxypyrazin-2-amine;3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-ethylpyrazine-2-carboxamide;3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxamide;3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-(methylthio)pyrazine-2-carboxamide;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethyl-3-(methylthio)pyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethyl-3-methoxypyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethyl-6-methoxypyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3-ethyl-6-(methylthio)pyrazin-2-amine;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-bis(methylthio)pyrazin-2-amine;6-(2,4-dichlorophenyl)-3-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-ethylpyrazine-2-carboxamide;6-(2,4-dichlorophenyl)-3-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxamide;6-(2,4-dichlorophenyl)-3-{[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]amino}-5-(methylthio)pyrazine-2-carboxamide;5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-6-ethyl-N′-methylpyrazine-2,3-diamine;6-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-N′,N″-dimethylpyrazine-2,3,5-triamine;or3-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-5-ethyl-N′-methylpyrazine-2,6-diamine,or a pharmaceutically acceptable salt of any said compound.
 32. Acompound of claim 1 wherein the compound exhibits an IC₅₀ for CRFbinding of 1 micromolar or less in a standard CRF binding assay.
 33. Acompound of claim 32 wherein the compound exhibits an IC₅₀ for CRFbinding of 100 nanomolar or less.
 34. A compound of claim 32 wherein thecompound exhibits an IC₅₀ for CRF binding of 10 nanomolar or less.
 35. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier or excipient.
 36. A method ofinhibiting the binding of CRF to the CRF₁ receptor, the methodcomprising contacting, in the presence of CRF, a solution comprising acompound of claim 1 with cells expressing the CRF₁ receptor, wherein thecompound is present in the solution at a concentration sufficient toreduce levels of CRF binding to the cells in vitro.
 37. A method ofantagonizing a CRF₁ receptor in a mammal, comprising administering tothe mammal, a therapeutically effective amount of a compound of claim 1.38. A method of treating a disorder manifesting hypersecretion of CRF inmammal, comprising administering to the animal a therapeuticallyeffective amount of a compound of claim
 1. 39. A method for thetreatment of a disorder, the treatment of which can be effected orfacilitated by antagonizing CRF in a mammal, comprising administering tothe mammal a therapeutically effective amount of a compound of claim 1.40. A method for screening for ligands for CRF₁ receptors, which methodcomprises: a) carrying out a competitive binding assay with a CRF₁receptor, a compound of claim 1, which is labelled with a detectablelabel, and a candidate ligand; and b) determining the ability of saidcandidate ligand to displace said labelled compound.
 41. A method fordetecting CRF₁ receptors in tissues comprising: a) contacting a compoundof claim 1, which is labelled with a detectable label, with a tissue,under conditions that permit binding of the compound to the tissue; andb) detecting the labelled compound bound to the tissue.
 42. An articleof manufacture comprising: a) a packaging material; b) a compound ofclaim 1, and c) a label or package insert contained within saidpackaging material indicating that said compound is effective fortreating affective disorder, anxiety or depression.
 43. A method ofpromoting smoking cessation in a human, comprising administering to thehuman in need thereof an effective amount of a compound of claim
 1. 44.A method of treating a disorder in a mammal, comprising administering tothe human in need thereof an effective amount of a compound of claim 1,wherein the disorder is selected from social anxiety disorder; panicdisorder; obsessive-compulsive disorder; anxiety with co-morbiddepressive illness; affective disorder; anxiety; depression; irritablebowel syndrome; post-traumatic stress disorder; supranuclear palsy;immune suppression; gastrointestinal disease; anorexia nervosa or otherfeeding disorder; drug or alcohol withdrawal symptoms; substance abusedisorder; inflammatory disorder; fertility problems; inflammatorydisorders; pain; asthma; psoriasis; allergies; generalized anxietydisorder; panic, phobias; obsessive-compulsive disorder; post-traumaticstress disorder; sleep disorders induced by stress; fibromyalgia; mooddisorders; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome;stress-induced headache; cancer; human immunodeficiency virusinfections; neurodegenerative diseases; gastrointestinal diseases;eating disorders; hemorrhagic stress; stress-induced psychotic episodes;euthyroid sick syndrome; syndrome of inappropriate antidiarrhetichormone; obesity; infertility; head traumas; spinal cord trauma;ischemic neuronal damage; excitotoxic neuronal damage; epilepsy;cardiovascular and hear related disorders; stroke; immune dysfunctions;muscular spasms; urinary incontinence; senile dementia of theAlzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis;chemical dependencies and addictions; osteoporosis; psychosocialdwarfism; and hypoglycemia.
 45. The method of claim 44 wherein themammal is a human.
 46. The method according to claim 45 wherein thedisorder is selected from affective disorder; anxiety; depression;irritable bowel syndrome; post-traumatic stress disorder; supranuclearpalsy; obsessive-compulsive disorder; anxiety with co-morbid depressiveillness; Alzheimer's disease; gastrointestinal disease; skin disorders;anorexia nervosa; social anxiety disorder; bulimia nervosa or otherfeeding disorder; drug or alcohol withdrawal symptoms; substance abusedisorder; inflammatory disorder; pain, asthma, psoriasis and allergies;generalized anxiety disorder; panic disorder; phobias;obsessive-compulsive disorder; sleep disorders induced by stress;fibromyalgia; mood disorders; dysthymia; bipolar disorders; cyclothymia;fatigue syndrome; stress-induced headache; cancer; neurodegenerativediseases; gastrointestinal diseases; syndrome of inappropriateantidiarrhetic hormone; cardiovascular and hear related disorders;stroke; senile dementia of the Alzheimer's type; multiinfarct dementia;and amyotrophic lateral sclerosis.
 47. The method according to claim 46wherein the disorder is selected from affective disorder; anxiety;depression; generalized anxiety disorder; social anxiety disorder;anxiety; obsessive-compulsive disorder; anxiety with co-morbiddepressive illness; panic disorder; mood disorders; bipolar disorders;post-traumatic stress disorder; substance abuse disorders; inflammatorydisorders; gastrointestinal diseases; and skin disorders.
 48. The methodaccording to claim 47 wherein the disorder is selected from affectivedisorder, anxiety, and depression.